Drug Design & Development

8/6/2019 Drug Design & Development

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Chader DrusDtscowry ..ign,.ndOevetopm.nra. lmpo anbe tLipophilicity . 53b. MeasurcmentlLipophit ic i t is. . . . . . . . . . . . . ._. . . . . 55c. Computeat ionfLogPValues. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61d. I \ ,4mbraneipophi l ic i iy . . . . . . . . . . . . . . . . . . .623. Effscts f lonization n LipophtticityndO.atBioavaitautity. . . . . . . . . . . . 624. OlherPropertieshat oflusnceOratBioavaitabitityndAbitity o

CrossheBloocl-Brainanir. . . . . . . . . . . . . . . . . . . . 6sG. Ouanlilaiive tructure-Activitytationships. . . . . . . . . _ . . . . . . . . . . . . . . . . . . _ . . . . 661 Hislorical . . . . . . . . . . . . _ . . . . . . . . . . _ . . . . . . . . . . . .1162. StecEllectsrTheTaf iEquaiionandOtherEquat ions. . . ._. . . . . . . . . . . . . . . . . . . .673. MethodsJsedo ConelatePhysicochemicatarameterswithBiologicalAci iv i ty. . . . . . . . . . . ._. . . . . . . . . . . . . . . . . . . .68a. Hanschnalysie:AlnoarMulr ipteogressionnaty$is. . . . . . . . . . . . . . ._. .68b. FreandWilsonor d novo \,lethod. . . , , , , _ . . . , , , . , _ . . , , , , , . . . . . ., , , ,70c, Enhancementactor- . _ 71d. lLlanualtepwise ethods:optiss petionatchmesndOthers 7le. Batch election ethodsralchwiseoptiss prarionatcheme,Clusrernalysis,ndOthe .. . . . . . . . . . . . . . . . . . .75

2,3 Gen6lReterencos . . . . . . . . . . . . . . . . . .47

ll z.r OrugDiscoveryDrug discoverys a very ime-consuming ndexpensive mcess.Estimates fthe avemaeimerequirdobringa drug o rhemarkerange rom 2- | 5 yars rana!emge o\r of $600_800million. For approximatelyevery10,000compoundshat areevaluated; animalsrudies. 0will make i to human linical rial\ in order oget t compoundn the marker. fie ct,nicaltrials consistofthreephases dor to drug approval:phase (generallya few monrhs o ayearanda hal0 evaluateshe safety, olerability (dosageevelsandsideeffects).Dharmacokineticpropenies.ndpharmacotogicatffecrsrl 20-t00 healrhy otunteers: haie I (abour _Jyears)assesseshe effctiveness f thedrug, determines ideefiectsand othersafelvasDects.andclarifieshedosingegimenna fes hundred Leased abents:ndpha.eU (;bour2_6)earsr sa larger ial $irh severa_lhousandadenrsn cUojcs ndhospiral\hateslablrshestheefficacy of the drug andmonitorsadvene rcactions tom long-termuse. Once he newdlllg application NiDA) s submined o rhe Foodand Drug Administration(FDA). ir canbseveralmonths o severalyearsbefore t is apFovedfor comnercial us.phaseIV studiesareconsideredo be fie esuhsound rha drug halha\already een owedonro hedruamarketand s in generaluse. Drug candidatesor rlewchefiical ent|ties,Nct, as theyare


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a!$oo 2I OrugDi5cov6ry Inien called) hat fail late in this Focessresult n huge,umecovered inancial ossesor the.ompany.This is why the cost o puchasea alflg is sohigh. t is not that t costs hat much omanufacturehat one drug,but that theprofits are neededo payfor aI of the dmgs hat failromake t to market after arge sumsof researchunds havealreadybenexpended.In general,drugsare not discovered.wllat is more ikely discovereds known as a leadcompound.The ead s aprototypecompoundhat hasa numberof attractivecharacteristics'such as the desiredbiologiirator phannacologicalactivity,but mav have otherundesirablecharacteristics,or example,high toxicity, otherbiological activities,abso.ytion difficulties'insotubility.or metabolism roblems.Thestructureof the eadcompounds modified by syn-ihesis o amplify thedesiredactivityand o minimize or eliminate he unwantedFoperties o^poina\NhercdruT cmd lat, a comPoundworthyofextensivebiological.pharmacological'andaninal studies.s idennfred- herla clinical druq,a ompoundady or clinical tdals' isdevelopd. ior to an elaborationof approacheso teaddiscoveryand eadmodification' wocommondrugsdiscovercdwithout a ead arcdiscussed

2.1.A DrugDiscoverywithouta Leada.1 Peniclllln.In 1928AlexanderFleming noticeda greenmold growing in a,ciltwe of ,tldp,]rlococc,rarrelr, andwhere he wo had converged,he bacteriawere ysed.L

l This led to the discoveryof penicillin, which wasproducedby the mold Actually' Fleming was not the first to makerhis obse ationi JohnBudon-sandersonhad doneso n 1870, ronica y also at St.MarytHospital in London, the same nstitution where Fleming made he rediscoveryll2lJosephLister had teated a woundedpatientwith Perirtli,.m, the oryanism ater found to be theproducerof penicillin (although hestrainsdiscovercdearlier thanFleming's straindid notFoclucepenicillin,but, ather,another ntibiotic,mycophenolic cid).After Flemingobservdthis Dhenomenon,e tried many times to rePeat t without success;t was his coneague'Dr Ronald Hare,l3'alwho wasable to reproducehe observation. t only occurred he firsttime becausea combinationof unlikely eventsall took placesimultaneously.Hare foundthat very specialconditionswere required to produce he phenomenonnitially observedby Fleming. The culture dish inoculatedby Fleming must have becomoaccidentallyandsimultaneouslyontaminated ith themoldspore.nsteadofplacing thedish n the elrigeratoror ncubatorwhen hewent on vacaiionas s nomally done,Fleming nadvertendyeft it on hislab bench.Wlen he retumed hefo owing month,he noticed he lysed bacteda Ordinarilv'pdcillin doesnot lysethesebacteria; t prevents hem ftom developing, ut it has no effetif addedafter the bacteriahavedevelopedHowever.while Flemingwas on vacation Julyto August) he weatherwas unseasonablyold, and his provided heparticular emperaturerequired or the rnold and he staphylococcio gtow slowly andFoduce the lysis. Anotherextraordinary ircumstancewas hat hepanicular strainof themold onFleming's culturewasa relativelygoodpenicillin ploducer,althoughmoststrainsofthat mold (Prnictlii"t ) producenopenicillin atall. The moldFesumablycame tom the abolatorvustbelowFleming'swhereresearch n moldswasgoing on at that timeAlthough Flerningsuggestedhat penicillin could be useful as a topical antiseptic,hewas not successfuln Foducing penicillin in a form suitable o treat infections.Nothingmore wasdoneuntil SirHowardFlorey at OxfordUniveniry reinvestigatedhe possibilityoforoducins enicillinn auseful orm. n ls40 heeucceedednproducing enicillinhatcouldLe aanuni,rereaopical5 and !slemicall).rtlbut the ull e\lenl oflhe valueof Penicillin


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t0wasnot revealed ntil the ate 1940s.t61lvo reasonsor the delay n the univenal utilizationof penicillin were the emergence f the sulfommide antibacterials sulfa drugs, 2.1i seeChapter5, Section5.4.B.2,p. 254) n 1935and$e outbreakof World Wd II.

,--\Hr\ ( 'FSOr\'ilR"*i1'*

No studies elated o thephafinacology, roduciion,and clinical aPplicarion f penicillinwerepmitted until after the war to prevent he Germanstom having accesso this wonderdrug.Allied scieniistswho were ntenogatingGeman scientistsnvolved n chemotherapeuticresearhwere old that the Gemans hought he niiial report of penicillin was madeust forcommercial casonso competewith thesulfa drugs.Theydid not take he rePortseriouslyThe original mold was Pdnicillium notatum,a stJain_thatavea reiatively low yield ofpenicillin. It was replacedby Peniciqiun chfsogenrn.LTrwhich had beenculturedftom amold growingonagapefiuit in amarket n Peoria,nlnoislnoi rnunyyean a.lut" *ged regading the actual structureof penicillin (2.2).131ut thecorrectstructwewaselucidatedn 1944with an X-ray crystalstructureby DorothyCrowfootHodgkin(Oxford); he systal structurewas ot actuallypublished ntil 1949 vlSeveral iffer-entpenicillin analogsR goup vaded)were solatedearly on; only two of theseearly analogs(2.2,R = PhOCH2,penicillin V; and 2.2,R : CHzPh,penicillin G) are still in use oday.

.-penicillin (F - PhocH,penicllllnG{R- CHrPh)

A.2 LlbriumThe irst benzodiazepineranquitizerdrug,chlordiazepoxide CI t7-chloro-2-(methylamino)-s-phenyl-3l- 1,4-benzodiazepine-oxide; .3;Libriuml,wasdiscoverealerendipitously.l0lDr Leo Stembach tRochewas nvolved n aFogram to synthesize newclassof tranquilizerdrugs.Heoriginaly setout oprepareserie. f benzhepro\dia/nes 2.4 .btrlwhenR wa'CH2NR2andR2 was C6H5, t was ound that the actual stmcturewas hat of a quinazoline3-oxide2.5).

Chaprr2 Drug DB@ery ltedgn, andDevelopmenr

s ! !* -n- \--a\ .",ii ^y' n-/\cx,' l 'coonH

. _NHCHI HC I

,-J*A'J:A"2.3

"2"t \ ,"?2.4

xlw\,'1o


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section 2.1 Drug Dl.cdry 11

itY-*"tz(o-

a'*


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DrugDiscoverY,esign,ndDevelopment

B. Leact iscovefy. . . , ' ' ; ' - ' ' ' l11. Randorncronlng . , ' " , '132. NonBndomorTarcstodrFocusd)crnlng ,' 143. DrugMetabol ismludios . . . . , ' - , ' - '144. Clinlcalbsrvatlons. " -' ' - ' 155. RalionalpproachesoLeadDiscovery ,' ,'16. . . . . . . . . . . . . . . . . . . . . . . . .172.2

B.c.D.E.


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12 Chaplor DrugDbcov.ry.D*ign..nd D.vetopmnrcHr:, .!)ar'f

r-dlazepam2.7

The initial diffiulry arises n the discoveryof the lead compound.Severatapproachescanbe taken to identify a lead. The fiIsr requirement or all of the approachess to havea means o assaycompounds or a particular biological acrivity, so ihar researchencantell when a compound s active. A ,ioaffn) (or sc,,err)s a meansof determinins in abiological ystem.elarjle o a conFolcompound.I a compound a. he desirea criviry.and, f so, what the ielative potencyof rhecompounds. Note tbe distincrionbetween heterms activity and potencj. A.rtl,ry is the particular biological or phamtacologicaleffect(for example,antibacterialactivity or antico$'ulsantactiviry)i pdrc, is the streng$of thatefft-Some screens re n virlo tests, or example, he inhibition of an enzymeor antagonismof a rcceptor; othersaft ,n yiro tesrs, or example, he abiliry of the compound o preventan inducodseizure n a mouse, n genelal, the in litl, testsaft quicker and lesseK)en_sive.Clurcntly, high-throughput creens lIS),Irrl very rapid andsinsitive ir vlrro screensinitially developedabout 1989-1991, hat now canbe carriedout roboticallv in 1536- or3456-well ilerplales n small submicrogmm)mounr5l compounddi55otu"an .uU-;-croliter volumes)arebecominguniversallyused.With theseulta-high-throughputscreeningapproaches,t is possible o scren 100,000compoundsn a dayl As we will sebelow.combinatorialchemistry seeSection2.2.E.5,p. 34) cansupplyhugenumbersof compoundsin a shortperiodof time, which, theoretically,shouldprovidean increased umber of ltr,i.e., compoundshat elicit a Fedetemined level of activiry in the bioassayand, thercfore,providemore eads.According to Drews,u2l he numberof compounds ssayedn a largepharmaceutical ompany n theearly 1990swas about200,000a yeari rhat number ose o5-6 million during the mid-1990s,and by the endof the 1990s t was >50 milliont How-ever, the increase n the assay ate did not result in a commensuratendease in researchproductivity,as measured y new compoundsentering he market. Of course, t can tale12-15 yearsfor a drug to reach the market, so Foducrivity in th early pan of rhe 2lstcentury shouldprovidea more accurate uler for success f drug disoverychangesmadeat the end of the 20th ceniury.Cunently, HTS appea$ to haveresulted n an increase nthe number of hils, but this may be becausemote lipophilic compounds,whih may havemore druglike Foperties (seSecrion 2.2.R2, p. 53), can be resredby dissolving themin dimethylsulfoxide(DMSO) ratherthan in water. Nonetheless,t is not yet clear if thisincrease n hit rate is translaiing nto a much greaternumbrof leads and developmentcompounds,tl3lAn exciting apFoach or scrceningcompoundshar might interactwith an enzyme n a

metabolicpathwaywas demonsrraredy Wong, Pompliano,and coworkeff fm rhediscov-ery of lead compounds haiblock bactedal cell wal biosynthesis aspotenrialantibacterialagents).t1al ondidonswere ound o reconstirute ll six enzymesn the cell wall biosyntheiic

____'_5


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Section 1 DrugDlscoverypathwayso that ncubationwith the substrateor the first enzyme eads o the formation oftheproductof the last enzyrnen the pathway.Then by screening ompounds nd ookingfor the buildup of an intermediate,t is possible o identify not only compounds hat blockthe pathway(and prevent he formation of the bacterial cell wall). but to determinewhichenzyme s blocked(thebuildup of an nterrnediatemeans hat the enzyme hat actedon thatintermediatewas blocked).Compoundsffeening also canbe caffied out by electrospray onization mass spectro-merylrsl (the echnique or which JohnFenn eceived he Nobelprize n 2002)and by NMRspecromety. r6lTightly boundnoncovalent omplexes f compoundswith a macromolecule(suchas a rcceptor or enzyme)can be observedn $e rnassspctrum.The afnniiy of ftel|Aand(a smallmolecule hatbinds o a receptor)canbe measuedby varying thecollisionenergy and determiningat what energy he complex dissociates. his method also can beused o screenmixnrles (a libnry) of compounds, rovidedthey have ditrerent moleculalmasses ndor charges, o the l,/z for eachcomplexwith dle biomolulecan be separatedin the massspectrometerBy varying the collision energy, t is possible o detemine whichlesrmolecute' ind o lhebiomoleculee'r.The rH \MR merhod xPloirshangeen erlherrelaxation ratesor diffrrsion ratesof small moleculeswhen they bind to a macrcmolecule.This method also canbe used o screenmixtures of compounds o determine he ones batbindbest-Once he screens developed, variety of approachesanbe taten to obtain a ead.As wewill seebeloq the typical lead compoundor a receptoror enzyme s thenatural igand forthe cceptoror substrateor the enzyme.Anothergoodsourceof leadcompoundssmarketedrlrugs.fl llr this case he argetwill generallybe well established, nd$e leadsfucture will beknown o bind well to the argetand o havegoodabsorytionpmperties.The main stumblingblock to the use of rnarketeddrugsas eadsmay bepatent ssuesor commercialization.fthe targetmacromolecules not knownor ifno new eadshavecome rom a marketeddrug,other aooroaches an aLen.

8.1 Random ScreeningIn the absence f i{nown drugsand othercompoundswith desiredactivity, a Iandom screenis a valuableapproach.Rdndom crceninqnvolvesno inteltectualization; ll compounds retestedn the bioassaywithout rcgard o the;r structures.Prior to 1935 thediscoveryof sulfadrugs),his wasessentiallyhe only approachi oday his method s siill an mportantapFoachto discoverdngs or eads.particularlybecauset is nowpossibleo screen uchhugenumbersof compoundsapidly with HTSS.This is the ead discoverymethodof choicewhennothingis known about hereceptor arget.The wo rhajor classes f materialsscreened resyntheticchemicalsandnatumlproducts(microbial, plant, and marine).An example of a random screenof synthetic and natunlcompoundswas her'waron cancel' declaredby Congress nd he NationalCancernstitutein the early 1970s.Any new compoundsubmittedwasscreenedn a mouse umor bioassay.Few new anticancerdrugs esulted rom that screen,but manyknown anticancerdrugsalsodid not show activity in the screenused,so a new set of screenswas devised hat gavemorc consistentesults. n the 1940sand 1950s,arandomscreenof soil samples y variouspharmaceuticalompaniesn search f newantibioticswasundertaken. owevet n this case,not only werenumerouseadsuncovefed, ut two mponant antibiotics.streptomycin nd he

13


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14 Chaplar OrugDl@ery lt rlgn, tnd DovoloPmnltetracyclines,were ound. Screening f micrcbial brolhs,particularstrainsof Strcptomlces,was a cominon tndom scfeenme6odologyprior to 1980

8.2 Nonrandom (oJTaryeted or Focu8ed) ScreningNonrandom creening,alsoc led taryetcdor octtsenscrcenine, s a morc Darow approachthan s random screening.n this case,compoundshavinga vague esemblanceo weaklyactive compoundsuncoverd n a random scrcen, or compounds containing differcntfirnctionalgoups than eads,may be ested electively.By the ate 1970s, heNational CancerInstitute's andomsueenwasmodified o a nonrandom cren ecause fbudgetaryandman-power cstrictions.Also, the single umor screenwas changed o a variety of tumor screensbecauset was rcalized hatcancer s not ust a single disease.

8.3 DJugMetabollsmStudisDuring drug metabolism tudies seeChapter7) rretdrolites (drugdegradationProducts en_er.ted in ,irr) that are solatedarc screenedo determine f the activity observeds derivedfrom the &ug candidate r from a metabolit.For examPle,he anti-inflannatory dnlg sulin-dac(2.8,Clinoril) is not the activeagent; hemetabolic cductionProduct.2.9, s responsiblefor lhe activity.tl8l

2,4

The nonsedating ntihistamineerfenadinehydrochloride(2.10,Seldane)was found tocause n abnormalheart hythm n someuserswho alsowere al:rngce(aln antiirngal agents,which were oundto block the enzyme hat metabolizesedenadine.This caused builduPofterfenadine,which led io lhe abnormalhearirhythms. Howevet a metaboliteof tefenadine,fexofenadin ydrochloride 2.11,Allegra),wasalso ound o be a nonsedating ntihistamine,but it canbemetabolized ven n thepresence f antifungalagents.This, then, s a saferdrug.Mtabolitescan be screendor other activitiesaswell.QHr

HO--H Ntrf6n.dln. Hcl2.10

1r


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;gD_ 21 DrugDls@ery 15

.\.t:r"t- -HoX .N--\zP(UoI'loxoi.ndln. HCI2.tr

8.4 ClinlcalObservatlon3Somerimes drug candidateduringclinical irials will exhibit more han onepharnacologicala.d!iry; thai is, it mayFoducea sideeffect.This compound,hen,can be usedas a ead(ot{rrh luck, as a drug) for the secondaryactivity. In 1947 an a ihistamine, dimenhy'lfnate,2.12.Dramamine)was estedat he allergyclinic at JohnsHopkins Univenity andwas oundd].oro be effecLiven relieving Palientwho suffered^.fromar sickne\sl.aurtherstudypm!ed rseffe(rivenessn ie treatmeDlf seascknes\rv andairsicloressrTl thenbecamethe mosrwidely usddrugfor the treatmentof all forrns of motion sickness.

\' )2.14

dlm.nhvdrh.le

Thereare otherpopularexamplesof drugsderivedfmm clinical observations.Bupro-pion hydrochtoride 2.13), an antidepressant rug (Wellbutrin)' was found to help patientssropsmokng and s now the Iilst dnrg marketedas a smoking cessationaid (Zyban).Ttteirnpotence mg sildenafilcitrate(2.14: Viagra) was designedor the treatmentof anginaandhypnensionby blockingthe enzymePhosphodiesterase-s'hich hydrolyzescy-clicguano-.in. -onopttospttat" (cdMP), a vasodilator hat allows increasedblood flow.t2u In 1991

sildenafilwent into phase clinical trials for angina. n phase I clinical trials, it was not aseffectiveagainstanginaasPfizerhadhoped,so t went back o phase clinical trials to seehowhish of adosecouldbe tolerated. t wasduring thatclinical trial that the volunteers eportedinleased erectile unction.Giventhe weakactivity againstangina' t was aneasydecisionto try to determinets effectiveness s he first treatment or erectile dysfunction.Sildenafilworks by themechanismor which it was designedas an antianginaldrug, except t inhibitsrhephosphodiestemsen the pnis(phosphodiesterase-5)nsteadof the heart (Figure2.1).Sexualstimulationcauseseleaseof nitnc oxide n thepenis

1?,"^I^Y)>"'


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16 Chaptor2 Drug Dlscwery, De3ign,andDevelopment

\ sDootbcCMP-----__t' muscle'_'---t_

.-AJs ---lq------.i- Nidc ondesynoase lsr ' ' r 'k 'IGuantlale cyclas IICTP+IGMP PDE54I inhibirsFlsure 2.1 > Mechanisnoi actionof sildenafl (Viagra)

Nitnc oxide s a secondmessengermolecule hat stimulates heenzymeguanylate yclase'which convertsguanosine riphosphateo cCMP The vasodilatorCGMP claxes he smoothmusclen the colp r .dttmos ,1, allowingblood to flow into thepenis, herebvproducinganerection.Howvet phosphodiesterase-sDE 5) hydrolyzes he CGMP,which causes aso-constrictionand heoutflowof blood rom thepenis Sildenafil nhibits thisphosphodiesterase,preventinghehy&olysis of oGMP andprolonging he vasodilationeffect

8.5 RationalApproaches o LeadDiscoveryNone of the aboveapFoaches o lead discoverynvolves a major rational componentThelead is just found by soeening techniques, s a by-product of dtug metabolismstudies,orfrom clinical investigations.s it possible o detrgna compoundhaving apa4icularactivity?Rationalapproacheso drugdesignnowhavebecomehe major routes o leaddiscovery Thefirsi step s to identiry the causeor the disease tateMany diseases, r at east he symptomsof disases, rise rom an mbalance eitherexcessor deficiency)of particular chemicals nthe body, rom the invasionof a foftign organism,or from aberrantcell gro*th As will bediscussedn later chapters,he effectsof the imbalancecan be corected by antagonism ragonismof a rcceptorGeeChapter3) or by inhibition of aparticularenzvme seeChapter5);foreign organismenzyme nhibition or interferercewith DNA biosynthesisor function areimpo(ant approacheso treatdiseases rising tom microorganisms nd aberrant ell growthGeeChapter ).Once he relevantbiochemicalsystem s identified. nitial lead compoundshen becomethe natural recptor igandsor enzymesubstntes.For examPle. ead compoundsor thecontraceptives+)-norgestrel(2.15,Orral) and l7o-ethynylestradiol(2.16' Activella) werethe stercidalhormonesprogesterone2'17) and 178 estradiol (2.18) WlHeas the steroidhormones .17 and 2,18showweakand shortlastingeffects, he oral contmceptives .15 and2.16 exert strongFogestationalactivity of long duration.


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Sedon 2.2 Lssd Modllicallon: Druq Dlgn and O.velopmenl 17

2.15 2.16

2,18At Merck it was believed hat serotonin 2.19)was apossiblemediatorof inflammation.Consequently, erotoninwas usedas a lead or anti-inflammatoryagents,and iom this leadlhe anti-inflarfinatory drug ndomethacin2.20, ndocin) was developed.t22l

2.19 2,20

,.4,-J

The rational approaches re directedat lead discovery It is notpossible,with much accu-racy, o foretel toxicity and sideeffects, anticipate ransportcharacteristics, r predict themetabolic ate of a dnrg. Once a lead is identified, its structurecan be modified unril aneffedive drus is obtained.

2,2 LeadModitlcation:Drug Designand DevelopmentOnceyour lead compound s in hand,how do you know what to modify in order o improvethedesiredpharmacologicalropefties?

.,.,22.A ldenlilication ot the Actlve Part:The PharmacophoreInteractionsof drugs with receptors,known aspidrltuco.bnamics, arc rcry spcific (seeChapter3). Therefore,only a smallpat of the ead compoundmaybe nvolved n the appro-priatereceptor nteractions.The relevantgroupson a molcule hat iDtemctwith a receptorand are esponsible or the activity are collectively known as rhephamucophrr. The otheratoms n the lead molecule,sometimes efe[ed to as the awophore. mav be extraneous,

1i


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18 Chaptd 2 Drug Dls.@ry D.!19n, nd DercloPrentSomeof the atoms,of couse, areessentiaio maintain he ntegrity of the moleculeand holdthe pharmacophoric roups n their appropriatepositions.Someof theseextraneous toms,however,mat be interfedry with the binding of thepharmacoPhore'ndthoseatomsnedto be excisealrom the leadcompound.Otber atoms n the auxophoremay be dangling nspacewithin thereceptorandarc neitherbinding to the receptornor Preventinghephama_cophoricatoms iom binding. AlthoughtheseatomsaPPearo b mocuous, t is important okrow which atoms heseare,becauseheseare he ones hat can be modifiedwithout loss ofpotency.As wewilt seeatq thereareotherasPectso leadmodification hatarc as mportantas ncreasingbinding to the taqet receptot suchaspdt nacot e/icr (abso4tion, distribu-tion, metabolism,ard excretionor ADME) Modificationofthe atoms hat arenoi intederingwith binding couldbe vr/ impo(ant to solvingphamacokineticspIoblems.By determiningwhich ale the pharnacophoricgroupsand which are the auxophoricgoups onyour eadcompound, ndof theauxophoricgroups'which are nterferingwith leadompound inding andwhich arenot detrimentalo binding,youwill know whichgroupsmustbe excisedandwhichyou can etainor modiry asneeded.One approachn lead modificationto help make hisdeterminations to cut awaysectionsof ihe lead moleculeand measureheeffectsof thosemodificationson potency.Consider his artificial exanple of how thismightbe done.Assume hat the addictiveanalgesicsmoryhine(2.21,R = R/ = H)i codeine 2'21'R : CH3, R/ : H), ard heroin(2.21,R = R/ = COCH3)are he leadcompounds, nd wewant o lorowwhich groupsarepharmacophoric nd which areauxophoric'

morphlne R = R' = H)codeine R= CH3,R'= H)hroin R = R' = COCH3)2.21

The morphin amity of analgesics indsto the l, opioid recptoN Thephamacophoreis known ;d is shownas the darkenedPsn in 2.21 A decreasen potencyon removalofa group wil suggest hat it may have teenpharmacoPhoric' n increase n potencymansit was auxophorican


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Scion 2.2 Leid Modltlo.llon: Drug te.lgn and D@loptrent

lcvorphanolF- oH)2,22

Possibly, he additionalconfofiBtional mobility alowed the molecule o approximatetsbioact e confomation (lheconformation hatmost efrectivelybinds o a receptor).Removalof half of the cyilohexene ring (alsonot in thephamacoPhor),eaving only methyl sub-stituents,givesbenzomorphan223, R : CH3).txl This compoundshowssomseparationof analgesic ndaddictiveeffects;pentazocine ydtocbloride 2.23,R = CHzCH:C(CH3)2componentof Tatwin) is lesspotent hanmorphine(aboutaspotentas'codeine), ut has amuch ower addiction iability. Remember,our goal s both to increase otencfand decreaseadverseeffects,such as addi.iive properties.Although this analog s not morepoteft thanmorphine, t is less addicting. Cutting away he methylnegmup of the cyclohexane usedring (2.24)also, surprisingly,has ittte effect on the analgesic ctivity in animal ests.

pnlazocln. CI F = CHTCH.C(CH3L)2,24

Again, hisexcision emoveshe rigidity of theParent tructure.Removalof all fused ings,for eiample, n rfiecase f meperidjDe215,_Demerol).ivesan analgesictill possessingl0-129oof theoveralpotency f morphine.l26llthoughheporencys lower, t cenainlywill be much easier o synthesizeanalogsof meperidine han of molphine. Even acyclicanalogsare active.DextoFopoxwhene (2'26, Dafloq againnote the side chain s left ina conformation o resemblehe structruof morphine) s one-half o two-thir& aspotntascodeine.Bothmorphineanddxtsopropoxypheneind to thep opioid receptot so heacdvityof dexrropropdxyphenean be ascribedo the fact that t can assume confomution relatedro that of the morphinephafinacophore. don't thint any of us, seingdextroProPoxyphenewritten in a more eneryetically avorableconfonnation,would ever make the connectionbetweenhis sfucture and hat of mor?hine.By cutdngpiecesoff of the eadcompound,tgivesyou new psspertiveson possibleactive structues, which should open up comPletelynewscaffoldso considern synthesis. notheracyclicanalog s methadone2'27,Methad$e)which s aspotentar analgesic smoryhine; he(-)-isomer is used n the reatmentof opioidabstinence yndromsn heroin abusers ecauset is eliminatd rom the body slower hanmorphine,allowing thebody to adapt o thefalling levelsof druggradually.

t9cttN

R\. xctz..-- z-c[,I l-'*)a\


14/37

20 Chdler 2 Drug DiscoEry. Deslgn,andovetopmenriH3._Y


15/37

seciion 2.2 L.ad Modification:orug DesignandDv.lopment2.2.8 FunctionalGroupModificationThe mportanceof functionalgroupnodification is demonstrated y 2'29. The antibacterialagent, arbutamide2.29,R = NH2), was ound o havean antidiabetic ideeffect;however tcould not be usedasan antidiabetic rug because f its antibacterialactivity, which could eadto bacterial esistanceseeChapter5, Section5.2,p. 231). The aminogroupof carbutanidewas eplaced y a methylgoup togivetolbutamide 2'29,R : CHI; Orinase)and n so doingthe anlibacterialactivjty waseliminated rom the antidiabeticactivity.

o,,-\R1 _TSO,NHCNHCH,CH,CH,CHTlolbut.midR=CH3)2,29

In somecases, nexperienced edicinal chemistknowswhatfunctionalgroupwill elicita oarticulareffect. Chlorothiazide 2.30, Aldocor) is an antihypertensive gentthat has astrongdiuretic effet as well. It was known from sulfanilamidework that the suuonamidesidechain can gjve diuretic (increasedudne excretion)aciivity GeeSection2.2.C below).Consequently. izzoxide 2.31.Hyperstat)wasprepared san antihypertensive rug withoutdiureticactiviiy.

2,30

aYY"",,*u{'2,31

Obviously,a relationshipexists betweenhe molecular structureof a compoundand tsactivity.Thisphenomenonwas irst rcalizedabout 135yearsago.

2.2.C Structure-Activity elatlonshipsIn 1868Crum-Brownard Fraser,t3oluspectinghat thequatemaryammoniumchancterofcurare,a potentpoisonknown sincethe 16tb century that was used on arrowheads,maybe responsible or its muscularparalytic Foprties (it blocks the action of the excitatoryneurotransmitter cetylcholineon muscle e.eptors), examined he neuromusaular lockingeffecisof avarietyof simplequatemary mmoniumsaltsandquatemized lkaloidsn animalsFrom hesestudieshey concludedhat hephysiologicalaction of a moleculewasa tunctionof its chemicalconstitution.Shortly hereafter,Richardsontsllnoted hat he hypnotic activityof aliphatic alcoholswas a function of their molecularweight Theseobservations re thebasis or future str.&ctureaciitiry relarionrldpr (SARo.Drugs canbe classifiedas being structurallyspecific or structurally nonspecific. ttr',/c-ntrclly specifc dru4s, wbich most drugs are,act at specific sites, such as a receptoror anenzyme.Their activity andpotencyare very susceptibleo small changesn chemicalstruc_hrrei moleculeswith similar biological activities tend to havecommonstructural eaturesStruct\rallf nonspecific tgs haveno specilicsite of action and usuallyhave owerpotencySimilar biological activitiesmayoccur with a variety of structures.Examplesof thesedrugsaregasous nesthetics,edatives ndhypnotics,andmary antiseptics nddisinfectants.


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chaprd 2 orug Dl.coery [t.lgn, and DevelopmenlEven houghonly apartof the moleculemay be associated ith its activity, a multitude ofmolecularmodificationscouldbe made.The hallmarkof SAR studies s the synthesisof asmany analoSs spossibleof the ead and heir testing o determine he effect of ssuctureonactivity (or potency).Onceenoughanalogs reprepared nd sufficientdataaccumulated, on"clusions anbemade egading structure-activity elationships.Unfortunately, ase f synthe-sis, ather hancogent ationales,s often heguiding orce behind h choiceof analogsmade.An excellentexampleof this approach ame tom the developmentof the sulfonamideantibactenatagents suua drugs).After a number of analogsof the lead compound sul-fanilamide (2,1, R : H; AVC) werepreparcd,clinical trials deGrmined hat compoundsof this generalstructue efibited diuretic and antidiabeticactivitiesaswell as antimicro-bial activity.CompoMds with each ype of activity eventuallywere shown opossessertainstructwal featuresn colnmon. On the basisof the biological results of geater than 10,000compounds, evenlSARgeneralizations eremade.t32l ndmicrobial agents avestructue2.32 R = SO2NHR/ r SO3H).

,\*rn,-1_/2,32

In 2.32. (1) the amino and suronyl goups on the benzene ing should be para;(2) rheanilino aminogroupmaybeunsubstitutedasshown)or mayhavea substituenthat s removedir rira; (3) replacement f tie benzene ing by other ring systems.or the introduction ofadditionalsubstituents n t, decreaseshepotencyor abolisheshe activity; (4)R maybeanyofrhealtematives hownbelow.but hepotencys reducedn mostcases;5)N-monosubstitution

,o+*1.oO*.E*.E*8-$'.(R = SO2NHR/) esults n morepotentcompounds, nd hepotencyncreases ilh heteroaro-matic substitution;and (6) N-disubstitution (R : SO2NRT), n general, eads o inactive

Antidiabetic agentsare compoundswith structure 2,33, where X may be O, S, or Nincorpomtdnto a heteroarcmatic tructuresuch as a thiadiazole or a pFimidine or in anacyclic structuresuch as a urea or thiourea- n the caseof uleas,theN-2 shouldcarry as asubstituent chain of at least wo carbonatoms,[33]HSO'NHC N\| | -B'x\ r

2.!l:!

Sulfonamidediuretics arcof two generalstructural yps:hydrochlorthi^zdes(2.34)andthe high ceiling typet3al 2.35).The forrner compoundshave l,3-disulfamyl groupson thebenzene ing andR2 s an electronegativeroupsuchasCl, CF3,or NHR.


17/37

Setion 2.2 Le.d Modlllcallon:Drug D.slgn and Dev.lopm.nl

R'N!SO, corH

ffi)

23

2.34

Acyloxyl csup Arntirli .tuitracyl gNupsMY. impsvul !.(iviry

Figur2.2 > SAR orP&lnaxelTaxoD

the hrgh 'eiling ompound' onrain *ulfamyl-J-carbo\,groups. ubsbruenl 2 . Cl.Ph,or PhZ, whereZ maybe O, S, CO, or NH andX can be atposition2 or3 and s normallyNHR.OR.or SR.tsslA more recentexample of a SAR is that of the naturalFoduct anticancerdrug pacli_raxel(2.36.Ta{ol), which was he first anticancer ompound ound to act by promoting heassemblyof tubulin into microtubules. herebyblocking mitosist36lAfter a large numberof modificationswere introduced,l3?lmany SAR (actually,structurFpdreno relationship)conclusions ould be made Figure2.2). A commonway to track the structuralchanges sw'trh heuseof molecularadiliry ndpr, structual drawingsof a ead compoundannotatedoshowwhere n the moleculespecificstructuralchanges ffect activity or potencymeasued na single ioassay.

o" lHo"o'\-n .,HO /:OB


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Chaplor2 Orug Dllcov.ry D6sl9n.and D.velopmonlFor large eadmolecules hat havebenextensivelymodifred, hesemapsconciselysum-marize a hugenumber of factsrelating structureswith their activitiesandpotencies.Effectscould nclude he abolishment f an activity,unexpectedoxicity, or largechangesn potency.Thesemapsmay depict he esultsof a onglasting drugdiscoveryeffort involving nunlercuschemists and he biologistswho do the sc.eens). heir main virtues are hat hey canpreventyour coworkers rom synthesizing nalogs hat havealreadybenmadeand ested,and hey

may dirdct the chemists'qeativify to unexplored egions of the leadcompound,yieldingnovel structual changes.The atroveexamplesFovide strongevidence o support he notion hat a conelation doesexist betweenstructureandactivity, but doeseach structure nteraci with only one receptorand ead to or y one activity?2.2.O Privileged tructures ndDrug-LikeMoleculesEvansand coworkers irst introduced he telm p,,lfileged rrruct!/rqr for certain molecularscaffolds hat appearo be capable f binding to multiple reeptor argets,and,consequendy,with appropdatestructue modifications, could exhibit multiple activities.t38lThe Merck$oup usedbenzodiazepines2.37) as the exampleof this phenomenon,which was earliermentionedby Aridns and coworkerswithout referring to them as privileged structures.t3elA numberof otherprivilegedstructuresare qrown.tl

Ro.- iloI I FNHcoR'

2.3?Thecommonalityofmolecular featuresn a vadety ofdrugs wasapparcnt y the revelationthat only 32 scaffolds describehalf of all known drugs.ta1lLikewise, a small number ofmoietiesaccount or a argemajority of thesidechains ound n drugs.la2l he average umberof sidechainspermolecule s four. If the carbonylsidechain s ignored, hen 737, of fte sidechains n dngs are rom the op 20 most commonsidechains.On.thebaiis of what s knownaboutpdvilegedstructures ndcommonscaffoldstructure,Ajay and coworkers roposedhatdrr,g'Ifendrs is a possible nllelnt Foperty of somemolecules,[43] nd his propertycoulddeterminewhich moleculesshould be selected or screening.They used a set of one- andtwo-dimensionalparametersn their computatioirand were able to predict correcdy morerhan907oof the compoundsn the Comprehensive edicinalChemistry CMC) databaseaal

Another computationalapFoach o differentiatedrug-like and nondnrg-likemoleculesusinga scoringschemewasdevelopdt45lhat wasable o classify correctly 83% of the compoundsin the Available chemicals Directory (ACD)ta6J nd ?7% of the compounds n the worldDrug Index (wDD.la7l A vadety of otherapFoacheshaveben aken o identify drug-likernolecules,t43lTherealsoaremanynonal g-Likemolecules hat showup asactivecompoundsn screens,but later are demonstratedo be alse posith,es inactivecompounds hat appear o be active


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Seclion22 LeadUodltlcailon: rugOslgn ndOv.lopmentin thescreen). hesecompoundsnitially appearo interactwith a variety of receptors ndarekno'rlnasptumiscuous in,JersprcrniscuousntaSottistufthey antagonizemany eceptors rpromiscuousnhibitorsifrheyinhibitmanyenzymet However, heyarenondruglike becauselheyact at a sitedifferent from that of thenatural igandor substrate, how ittle relationshipbetweenstructue and activity, and havepoor selectivity for a specific rcceptoror enzyme.As a result.much time is wasted ollowing up on the activity of thesecompounds,ater tofind out that hey are nactive.Shoichetandcoworkers howed hat manyofthese compoundsaJeactually aggregatesf molecules,and i is the aggregatehat produces he false-positiveacriviiy.tlgl ff theconditions of the screenarechanged,heseaggregates issociate,and heindividualmoleculesanbeshownobe nactive

2.2.E SiructureModificationso IncleasePotency nd-theTheraDeuticndex -i7How do vou know whal moleculai modificationsto nake in order to fine tune the leadcompound?Theprecedingsectionmakesclear that structuremodificationsare the keys toactivity and potency manipulations.After ye3rsof structure activity relationship studies.variousstandardmolecularmodificationapprcaches avebeendevelopedor the systematrcimprovementof the theldpeuti index(zlso called he hetupeuticntio). whi'ch s a measueof rhe safety of a drug as determinedrom the ratio of the concentrationof a drug thatgivesun{tesirable ffects o that which givesdesirableeffects.The therapeuticndex canbdetermined y any method hat measures ndesirable nd desirabledrug effecls,but often itis takenas he dose-limiting oxicity versus hedesirablepharmacological ffect n ananimalmodel(preferablyhumans).For example,he herapeuticndex could bethe ratio of the LD5o(the ethal dose or 507, of the test animals) o the therapeuticEDso(theeffectivedose hatproduces he maximum herapeutic ffect n 509.of the test animals);a toxic EDso thedosethat producesox;city in 50Eoof the test animals)may substitute or the LD50. The lsrgerlhe therapeuticndex,thegreaterhemargin of safetyof the compound.n other words.youwould like to have o administergram quantitiesof the drug before any undesirableeffectsareobserved. ut administeronly milligramsof the drug o attain he desirableeffects.Thereis no specificminimumvalue or a theraPeuticndexthat must be httainedbeforea drug canbe apFovedl it depends n the diseasehat is being treatedand whetherother therapiesarealreadyavailable.A low therapeuticndex s tolerable or lethal diseases,uchas cancerorAIDS(maybe venas ow as 5),especiallyf no oiher reatments available r f thesideeffect s rninor comparedwith the reatmentbenefit.For ess breatening iseases,herapeuticindiceson the order of 10 100 nay bereasonableAs an example, he therapeuticndex brlheantitumor gent hlorambucil2.38, eukeran)s 23 tsol heMerck ndex s agood ourcefor obtaining Dsodata or drugs n animals.

HOOC cla\ /-\chbrambucll cl2,36

A number of stiictural modification methodologies lbllow


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26 Chopler2 Drug Dlscovery,Deign, and D.veloPnenl

r23456?89101112C chain Lergth

Flgure 2.3 > Generaletr@l of ctrbo. chain len8lh o. dtug polency

E.1 HomoloEationA honolosow senes s a group of compounds hat differ by a constantunit, generallyaCH2 group.As will becomemore apparert n Section2-2.F2, p. 53, biological propertiesof homologouscompounds how regularitiesof increaseand decrease. or many seriesofcompounds,engtheningof a satuated ca$on side chain from one(methyl) to frve to nineatoms pntylto nonyl)producesan ncrcase n pharnacologicaleffects; uther lengtheningresultsn a suddenecreasenpotencyFigue2.3).lnSection .2.F2.b, .55.I show hai hisphenomenon odespondso increasedipophilicity ofthe molecule opermit penetation ntocell membmnes ntil its loweredwatersolubilitybeconesproblernaticn its transporthroughaqueousmedla. n the caseof aliphatic amineqanotherFoblem is micelle formation,whichbeginsat aboutCt2.This effectivelyremoveshecomPoundrom Potentialnteractionwith theapFopriatereceptols.Oneof, if not the,ear_liestxamples f thispotencyversus hain engthphenomenonwas reportedby Richardson,prlwho was nvestigatinghe hypnotic activity ofalcohols.Themaximumeffectoccuned or l-hexanol to l-octanol: then hepotencydeclinedon chain engtheninguntil no aciivity was obse ed for hexadecanol.A study by Dohmeet dlts2l on4-allryl-substitutedesorcinolderivatives howed hat thepakantibacterialactivity occurred with 4-n-hexylresorcinolGeeTable 2.1),_acompoundnow usedas a topical anestheticn a variety of throat lozenges.Funckeet dll53l found thatthepeahspasmolyticactivity of a seriesof mandelate stersoccurredwith thet-nonyl ester(see able .1).

E.2 Chain BranchingWten a simple ipophilic rclationship s important, as descnbdabove, hen chain branch_ing lowers hepotencyof a compoundbecause branchedalkyl chain s less ipophilic thanthe correspondingsfaight allvl chain asa result of larger molar volumesand shapesofhanched compounds.This phenomenons exemPlifiedby the lower potencyof the com-poundshaving isoalkyl chains n Table 2.1. In this cas,pharmacokineticswould be theoverriding actor or poteny.However,anotherexplanationor lowerpotncywith branchingcould bepharmacodynamics;hainbranchingmay nterferewith receptorbindlng.For exan-ple, phenethylaminePhCH2CH2NH2)s an excellentsubstrateor monoamineoxidase,but


21/37

secrlon2,2 LedModltlc.llon:DrugDg3lgn.ndDevelopmentTABLE 2,1 > Eflecl of chaln Longth on Pot6ncy.Antibacterial activity of 4-tFalkylresorcinob andspasmolytic gclivity ol mandelat steB

27

liYo'dYOH

-olt$ir.o,*% SpasDolltic activiq/

methylehtylr-prcpyt

,-heptyt

' -propylt-htylt-hexyl

0.3o.79.828355l130190

3',7220.98.328

;22335l300000

15.223.82:7" Relativeo 3,3.5-trimethylcyclohexdol.elat 100%.

s-methylphenethylamineamphetamine)s apoor substate.Primaryaminesoften arcmorepotent than secondaryamines,which are mor potent ihan tertiary amines.For example,the antimalarialdrugprimaquinephosphate2.39,Primaquine) s muchmorepotent han tssecondary r tedary aminehomologs.

cHro

Major phamacologicalchanges an occw wilh chainbranchingor homologation.Con-'ider the lGaminoaftyphenothiazines (2.40,X : H). w]en R is CH2CH(CHr)N(CH:)z(promethazineHCI; Phenergan), ntispasmodic nd antihistaminic activitiesprdominate.However the straigtt-chain analog2.40 willl R being CH2CH2CHTN(CH3), promazine)hasgeatly reducedantispasmodic nd antihistaminicactivities, but sedative nd tranquiliz-ing activitiesaregreadyeDhanced.n the caseof the bnnched chain analog2.40 with R equal


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ff:t#$$lx::'j,,$ilil'l*ffiff[{l*Hi:l*nChaptr2 Drugoi6coverv'Dellgn' andDvebpment

ll

i,:,ffiifiTii*:fl31?$$.[#i1,E.3 Ring_ChainTranslormationsAnorheroJcarronhar.*b:"*^d':l T ::1,j;TxT::1il:H",1;:#.'::fi""l;li:i'::*::"'i.*1"?ii{'ii::ll.''j:il'.*;;-, il";;;;;,and40 ' cr; : :1: i; . ; , ; ; . ;varenta'( 'anquiri/er' ' |nanimarresr' thebranchedmerhvrgroup::*:tt.*Hr*:nr*xl1l,i'Jli:;:il",il:'1"",1"';-l;"1"11?'ill'lilililactivity in man

r-Y\-(.^'.,-l l242

G"DI l l

2,41

"#lnlr:::lrfr,*#:#i:*n#iltthii]6:+1;;::J:Tffii5j"x#:ilil:ffi'*."tr;,il::"1il##,"'*t;35;;frff 'll'"'S,$.",1**un'.^""-'t'::I."1.,:*::l::1"'i::Tffi: ;llH.:iilill;:iil:ilTfT:j:I :J:llllr''"lillTi.;;;.,u,.' n',n.,'.',."n''uu"u


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S.tr 22 lad ilodlidrbn: Irrug Dalgn nd atevelopm.nt

TABIE 2.2 > Classlcal lso3telca

29

: L;:ldr d(m dd groups

: *-ddtuc andS6ups

i Tilzlar :hs md sroups

II

rd rorniring) activity is greadyenhanced.n ihis case,howevel an additionalmethylamino!re@ r! also added,which mayhavean effect n changing he activify

EJ Bkisoeterish.lirpr..'pr aresubstituents r groups hat havechemicalor Physicalsimiladties,andwhichrrece tioadly sirnilarbiologicalpfopIties.tsalBioisosterism s an mportant eadmodjtr-@ a+proachhalha\ beenshowno be useful o artenualeo\icity or to rDodify he activity,f r lcad.dd may havea significant ole in the altemtion of pharmakineticsofa ead ThereG dlssi'd isosteresl55,s6lndnonclassicalsosteres.tsTln 1925Grirnrntssl dmulated the@ displacenentaw to describe imilaritiesbetweengloups hat have he_s^ameumber* ."aaoe itectrons, lut may have a different numberof atoms.ErlenmeyerlseJater rede_Lld ioneres asatoms,ons, or moleculesn which theperipheralayersof electrons anbe.ffir--d ro be idendcal.These wo definirioDsdescribe lass/cal irorl?rcrl e).amples rcturiElabl 2.2. Nonclassicalbioisosteres o not have he samenumberof atomsand dodr& $e *eric andelectronicnles of theclassicalsosteres, ut doproducesimilarbiologicalEiE L\amples of Lhese re shown n Table 2.3.Ring-chain ratrstonnations lsocan beffirt-Fl ro be isosteric ntercharges.There are hunabeds f examplsof compounds lnttrfu ts ! bioisosteric nterchangeJml ome"',mFles are sho*n in Table2.4.

1I

(..3., bonrcDe,diidpdenc)(0.9.,bellae, plddine)


24/37

Chaptr2 Drug Dlscovery D*19n, and ltevelopment

TABLE2.3 > Nonclassicalsosteres

fil))L


25/37

lFr ;i Ld Moditicatlon:Drug DesignandD.velopment

EE 23 > Coiti {e,l

31

o-/i\NRR'

.-'t N-s\\ ll ,JiDR OR

"-dN.^d:

CN,N-

7'c'N-R

R',-\t r

r-dINF'N'Nr,N.2--n

Ia\>-,,/-d

Ztlo*

qo ""n ,,"-Y)x=O.NRN(CN), C(CN)r

-\'IlcN

:I

j cr, cr

jox!: ,,o'.

*t""*1"n, *-SozNHu,[.r.N'II ' -NH,CN

5


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32IABLE 2,3 > Co tiaued

Chaptr2 DrugDbcovery D.5lgn, rnd tt EloPmnl

l ("r l Y . ' f l YNOr R 'NR:|Fl aS l^ r rt.' T-tr T-o.. r-o , n-or r(r., I l l . t , . . | , ) r . / LZ UN LNI LN2v I t"- \N'/ L-i/ \N*, "r"t *"o

| r3 l o - ' *- , i " ' , " to\2 o'" ' ""f1__l *--;/-o^^ C-o-'" "'1Ao *A*'A *,l iRF6; -{-)-EF

It is actually quite surprisingthat bioisosierismshouldb such a successfulapproachto lead modification. Perusalof Table 2.2, and esPeciallyof Table 23' makes t clearthat in making a bioisostericrcplacement,ore or morc of the following Parameterswill

Bioisosterism,however,alsdcan ead to changesn activity or potencyFor example' fthe sulfur atomof thephenothiazine eurolepticdrugs(2.40) s replacedbv {H=CH- or{H2CH2- bioisosteres,hen dibenzazepine ntidepressant rugs (2'43) result A changein enzymeaffinity also can be observed.For examPle,when the thi^zolone ring in- aseries f anti-inflammatorycompounds electiveor the cyctooxygenase-2sozymeoverthecycloorygenase-isorymeseeChapler . Section 5 8 2 b p 280rqas (ubslituled y,anorazolonei ng i.e.. heS a s eplacedyOr. heseleclivityor he wo soz)me' te!er.ed " '

R2,43


27/37

Lad Modfil@rbn: Orug Oellgn.nd It votopmsnt

TABLE 2.4 > Exampt$ ol Blobogteric Anatogs

33

| . Neumleplis (dtipsychodc)

2. Alli.inflrnD ory rgeDas

oX= ,/C\ d CHCIi

xo

= NHOH, N_N--{ )\ ,fi

Y=CHrO Z-CtY=F z =SCHrGul indac)

X = NH,O,CH,

-< ) c=DH\H

lhtrge: size, shape,electronic distribution, ipid solubiltty. watersolubility, p1


28/37

34 chapier2 orugDlsco{orytellgn' tnd oovelopmenr2. Receptorntemctions lf themoietyreplaceds involved n a specifrcnteractionwith a."""p- o. "*V.", tft"" all of theparameters xcept ipid and watersolubility will beimportant.3, PharnatoLinerirsH the moiei) rePtaceds necessar)or ab'orption ranrponandexcretion of the compound,&en liPophilicity, hyftophiticitv' pra' and hydrogenbondingwill be important.4. Metabolism. l the moiefy eplaceds involved n blocking or aidingmetabo]ism'hen&e chemical eactivitywill be imPortant

It is because f thesesubdechangeshat bioisosterism s effective This approachallowsthe medicinalchemist o tinker with oirly someof the panmeten in order to algment tbeDorenct,lectivrty.andduralion f action nd o reduceorcir) Mul!iplealteralronsa)be1."...i* . --i.rU"r-ce effecls.or examplel modificalion l a lunclionaliryn!olved

inLinairuat ,oaect .u'e.rhel ipophj l icrrvof Inemoleculelherebyreducingitsabi l i t ) ropen-etrateceli walls and crossothermembmnes,he moleculecanbe modifiedat a different sitewi$ a ipophilicgotrp o increasebsorprion utwhere an hese ioieo'tericeplacement'* maael ptrarinacopnoretudv seclion2 2 A p 17'couldhavdenrifiedho'egrouPson lhe ead ar couldbe modifiedwilhoutan effecton receptor indrng thescrssronsnaIled o lillle changen porency)Those re heposjtron' at caD e

qafel)modinedMod-ifi-carions f rhis ;n. h;wever.maychangeheo\erallmolecularbape nd esult'n dDolheruyr4.E.5 CombinaiorialChemiltrya. GenralAsPeclaConbinatunatchenistrynvohe' heslnthesis rbiosvnlhesisf'n?"ical /i'wi?srafamjly"of comooundsavinga cenajnbase hemical tructurer f molecules,tolIt.plTott o'biologiiat creerung.aniculartyor eaddi\covery r leadmodihcalion '' llprcarD rnesechemicalibraries repreparedn a sysremaricnd repetilive ay b) {ovalentassemoiyoi tuiaine bloc*s(v^tiou; reactantmolecules hat build up pafis of the overa structure)a ni* u "Au".r" urruy of moleculeswith a commonrcaf''d (the Parentstructure n thei"tiifr "i *rno*"aO me advantage f this metbodologys that it is caniedout on a solidi"ir"i".ri.i t,ioo*. - ,rtar 'olati;n and

purincarion f lhe producr f each eaction anri" "LJ.*.4 dt .i.pr. nlrauonandwa'hing $ilh a latiety o[ solvent' ) f the

pol]mencsuooon o uhich thebuildingblockshavebeenanachedBecau'e f lhe nsolubrl'ly l the*iiln.r. ."."tft;ne ".t uttac-hedo hepolymer ' removedwhichailow\ theuseofexcerr;;;i;; d;". i'h. synrheLiceactionsThe d;sadvanrasesr rhis methodolo$are !hai6"uftv in ""nfing op tl" reactionsand he sluggishnessf reactions'An altemativestrategyrcovateh cauenei,ie,ndlo8)'rt ro car4 out he eacrionsn solution ithercesseagenr'"ft"i i" J." *"i*g"a *ith apolymenc*upponedcavengerfter he eaclionis

omPlereL{Fisure2.4). n thisapproach.ilttatjon emo! s he excesseagent tlachedo tnescavenger.11""-"t f"""." ,ft"'"i"auct in solutiont63lAnother appmachs to usepolymer-supportedI*i."ii *lr, sitrrion ,.a.rion' To avoidproblem ol hererogeneousolvmer eactions..iiti. oort.,r'vr.". rv.ol olvmenan e sed

6al-- A;;" air.t.i... u.ong the \atious combinatonaipproacbe' re he solid rlrp-oon used.he method' or a'semblinghe buildingblocks the state rmmob 'ed or.rn.otunonr nd numbersa fraclionof lhe lotal Ubmryor individual ntitier) n shrcn $e


29/37

+l:LT 2 2 Lead Modillcallon: Drug D*lgn and ltevelopmoni 35

h

oot/ /-b6*.HCt

Figure 2,4 > Use of polymq-bomd retgents 10 scavengeexce$ taciants in a re&lio.

I'b de. are screened.n.l rhe manner n which rfie struclures [ acnle compounds redetermined.Tlre nurnberof possibledifferent compoundsn a ibrary (N) is detemined by thenumbrof building blocksused n each step(r) and he number of synthetic steps r). If an equalnunber of building blocks is used n eachsynthetic step, hen Equation 2.1 holds. ff thenumber f building locks n each tep s varied e.9.., c, andd for a three-stepynthesis),drenEquation2.2 s relevant.

-{ combinatorial ihary of all of thepentapeptideshat comprise he 20 commonly encodedamino aidswouldbe /r' = 20r or 3.2 million differentpeptides.Combinationalchemistryoriginally was used o make peptide ibranes, but now is most cornmonly employed forrhe synthesisof large arraysof diversenonpeptidicsmall molecules. t is only because frbe discoveryand development f HTS techniqueshatcombinatorialchemistrywas able orhrive.Unless herewerea method o test3 milljon newcompounds eneratedn a ibrary in ashortperiodof time, hercwould be no advantageo beingable o makethatmanycompounds.Theo;edcalestirnates onclude hat there areup to 10130 ossibledruglike moleculeswithmolecularweights below 800,but this amountexceeds he massof the universe.The muchlower estimateof 1060moleculesl6slwould stitt tate over 1o5l years o synthesize, ven fa million compoundsa day werepreparedll66lTherefore,evencombinatorial methodsareinconsequentialclative to the total numberof compoundspossible,but the belief is thatir can approach he theoreticalvalue of compounds uickerthan by conventionalsyntheiicmethods.Howevet thediversityof moleules hatcanbe attainedby combinatorialchemistry

G'-.:.-Jl

(2.rt(2.2'


30/37

chapler? DrugDlscovory.e6lgn.ndDevelopnnl

ma\ noL oual onventionalynlheticpProache'hebegnnj g' of combinatorialhemi\lr'areat(ibuiedo ft'rkal6/lwithapplrcalioDsn peptide') nthe'i\b) cevsenand osrorKers'andHoughlen.loelhesenidaleffodsn Peplideibrarv vnrhesisere ollowedDy


31/37

secrion 2.2 L@d Modlncallon:D.ug D8lgnand DevloPmenr 37

lne-Kdl " I:n!!!l!!l i

l

., d and split) nro 3 equal

ult ll

utut"t

orbinq hoiogqte, and didde d

i l l

Ilihra4 ol

edPepbda gdP.Plids 9 tiPPttds.mbine and honogtuq thcn cl@vb giw a snbhdonal lbnrv oL d

Schgmo2.2 > Solid-ph4eynthesisf s combinatorialibrarvof aUPosible ripeplidesfhntidine

to be best(Figure2.5B). Again, an aliquot from eachnrbe.after cleavagerom the resin' isassayed, nd he best aminoacid at thepenultimateposition s determined.This process srepearednlilrhere re20rube\. ach ontainingnlyoneN acer)herapeptide.nd hebesroi$e 20 s dererminedyar'ay.Follo$inghisptrcedure.hemo't polenl nragonisrol t}|e,. opioid receptoround up to that ime was dentified(Ac-Arg-Phe-Met-Try-Met-Thr-NH2).The entireprocessookabout2 monthsl Canyou maginehow long this would ta,keo carryout one compoundat a time'?This methodologysoundsoolproof, but it is not. Sometimes,he mostpotentaliquot islesspotent than what was observedn the assaysrom the prcvious teration. How is thatpossible,becauseheprevious terationhad to havecontainedall of thepeptidesn thenextireration and hen some)?This is a cornmonphenomenon ith assayingmultiple compoundssimultaneously,articularlypeptides.OneexplanationsPePtide-peptidenteractions n thenext teration thereare fewerpeptidesn the tube ftan in the previousassay: he necessarypeptide-peptide nteractionmaybe lost in the later assay.Possibly he active componentsreally two or more ntemctingpeptidesand one s removed n the next itelation. Or maybe

I t r


32/37

38 Chapler 2 DrugOl.coEry, D.slgn,.nd Dovglopmenl

2.3.II

'-AC-AITXXXXX-N-MBHA EsinHlr'-Ac-CyrXX)C(X-N-MBHA EsinHai-Ao-Ai8.XX)O(X-N-MBHA EsinH

20.,V-A.-ThrX)C(XX-N-MBHA EsinH

(B) l, /V-AC-Aig-AIa-XXXX-N_MBHA sing2. X Ac ArfCysIntGN-MBHA $in3. ,-Ac-ArrArs XXXX-N-MBHA esinIHIII

20. r'-Ac-Ars-I1tr-XXXX-N-MBHAsinH

Each lbe onlains a mbi.atonat lbEry of 3.2x lddiffeFnl MBHA resin-boundv-aelylhexapeprid* rllhaving hesme miro acid ar heN teminus,

Eacb ube contaiN a conbindorisl librEJyol MBHAein-bound t-celyhexipeprides all with A. Ary al thN-leminus, oneol the 20ahino sids al tnepe.utinai.N-leminus.dd a mdon mixtuE of all po$ible adino

Flgu6 2.s > Conbinatorialsynlhesis f .ll of the r' acetylhexapeptidesf ihe 20 comonly encoded

there s a confornational difference n the activepeptideas he numberofpeptidesdiminishes.Peptidesenerallyo notmakeuseful rugs, sdiscussedn Section .2.E.7, .47.c. EncodlngComblnatorlalLlbrarlesBefore tuming our attention o the more important nonpeptide ibnries, let's consider analtemativeapproach o the dentification of the mostpotentanalog n a combinatorial ibraryoiher than repeated tentions until one compound emains.A more rapid approachwouldbe to test the entire ibrary at once and dentify theactive componentof the ibrary directly.As mentionedabove,with large ibraries of complex molecules i is not readily possible odetermine hestructureof theactivecomponent.n that case, ncodingmethods reneeded.lT3lThis is similar to the way n whihFoteins areoften sequencedn biology; theprotein s notsequenced,ut the gene hat encodes he protein s.l79lAlthough thestructureof tlrc actualcompoundmay not be direcdy elucidated,certain tag molecules hat encode he structuremay be determined.lsol ne mportantapproach hai nvolves he attachment f uniquearmysof readily analyzable, hemically nen, small molecule ags o eachbad n a split synthesiswas reportedby Still andcoworkers.l8'l deal encoding ags must surviveorganic sy hesisconditions,not nlerferewith screening ssays, e readilydecodedwithout ambiguity.encodelarge numbersof compounds, rd the test compoundand the encoding ag must be able tobe packed nto a very small volume. In the Still method, groupsof tags arc attached o abead at eachcombinatorialstep n a split synthesis.The tags createa record of thebuildinBblocks used n that stp. At the end of the synthesis, he tagsarc rcmoved and analyzed,which decodes he structureof the compoundattachedo that bead.As dpicted n Scheme2.3, one or more readily cleavable ag molecules Tagsx) are attached o about l% of thepolymer bead sites (about I pnoybead), and theseencodebuilding block I (BB1). Then


33/37

sdion 2.2 !..d lllodllicattonl Drug tetign tnd D'rclopment 39

(Berdl-BBr-BB2 -BB3

',1" i,o"'** r,fi" i '*x| "**"*^"6A* * *e,: BBi ' f.s,x , rassl + rr - secbo@c'pb, I i'd N r'\ md'o@lek-,/ .-

*"' b di' bLildns blocltt

Sctrem. 2.3 > Still nethodolo$r fd encodingconbimtdial PePti'le ibidies on aPolvmq b3d

one or moreothercleavableags TagsYr ranachedo encode uiidingblock2 (BB2)followedbv Tassz o encodeBBl. aodso foflh Althougha different ag couldDeusedfor eachdildin; bloc , it is moree ficientuousemixtures f tagsbecauseu-\turesl rvdifferent ags a-nepresentd different ynlhese\l ith ust l0 iags 1024 2'") synlhesescan be Derformed.-- ftre'tue, ne"a ro U. cherniially inen and etiablyanalyzed n lhe femtomolarscaieTtvoexarnoles-otagsare2.44and2145The hiny 2'44 agsarepbolocleavable'nd h-lo(y2.45 aesareoiidativety cericammonium itraE)cleavedThereleasedagsareanalyzedby capJtary as bomarographysing lecnon aDtureeteclionl ll ol the ags ave lEeFunL etenLioritimes.Ortrersensitivedeiectionmerhods re luorescence-basedPLCIs2landcC rnassspectronetrYE3l


34/37

Chaflor2 DrugDllcovry. 3lgn,nd DddopnnrIfyou areusing he split synftesismethod,how will youknow which of the argenumberofpolymerbeads asanactivecompound?Oneapproachtsals to chemicallyattacha comnercialdye o the a4et receptor.The assays runwith th ibrary still attachedo eachpolymerbead.If a compoundbinds to ihe dyelabeled receptor, hen the bead o which the compound sattachedwill take on the color of the dye, and the colored beadscan be removedmanuallyanddecoded. he ntensity of the color in the bead s an ndication of the ightness f bindingof &e compoundo the receptorLefs gothroughanexample,which may make hisprocess learer ormaybenoo. A combinatorial ibary of all of thehexapeptides f seine, leucine, ysine, soleucine,andglutamate(56-or 15,625-nenber ibffy) is Fepaftd with the appropdate ag moleculesat each tra-tion. To do this you ned6 x 3 (3-bit binary code) or 18different tag molecules.Tags I 3are only used o definebuilding block 1, tagsH are or the secondbuilding block, tags?-9for the d rd, tags 10 12for the fourth, tags 13-15 for the fifth, and ags 16-18 for the sixthbuilding block. Arbitrarily assigna 3-bit binary code o eachaminoacidbuilding block, forexample,001 Ser,010 Lu,011= Lys, 100= Ile,and110 Glu. fa tag s used, trepresents inary bit 1 if no tag s used. t meansbinary bit 0. Because eptidesyntheses retypically done on a resin to which the C-teminal amino acid is attached, nd hen couplingoccursback to the N terminus, ags 16-18 encode he N-terminal amino acid, and tags1 3encode he C-teminal amino acid. LeCs say an active bead s identified. andyou want tokrow what hehexapeptide tructure s. The agsare ernovedrom the bead by photolysisoroxidation.dependingon which linker was used). he carboxylic acidproducedby cleavagestrimethylsilylated o make t morevolatile, and heelectroncaptureGC s run. n lhis example,let'ssay hat ags1,2, 5, 6, 8, 9, 12.14,and16weredetected.heseags anbdecodedoidentify the hexapeptide s shown n Figure 2.6.Another encodingprocesssegregateshe test compound iom thecoding tag moleculeby attaching he test compound o the extedor of the beadand the coding tag molecule othe ntenor of the bead.l85l his Feventsthe tagrnoleculesrom interfering with binding ofthe test compound o the target receptor.A polymer bead systemwas developd n whichonly the surfaceof the beads exposd o an organicsolvent hat contains he organic-solublederivatizing reagenti his allows a nonpeptidic est compound o be constructedwhile theinterior of thebead emains n water without denvatizing eagent.The codin8 molecule s a

'fas l, Trg 2.1t0t 0ttt

Tag .Tag9, Tag 2, Tag ,1 Tagt6ott 001 010 100I I I l t

noTrgT noT,gl0 nolagl l no'r1g 7

100-010001 0l l 0 l l l l0 = Ile-llu-Ser L)'s Lys CIU(lromhl 3-blr ln.rycod$ iniiiatty $tgnedwhenmakhg he ibra ry)

Flgu.e 2.6 > An examplef encodinghestructurefa peprideouid o apolymer ead y heSlill


35/37

i4. 22 L6.d ilodlllcrtlon: Drug t dgn .nd Dcveloprn.nl

--Er:ie. whrchcan be synthesizedn the aqueousmediun of the intedor of lhe bead.Once:e r r' e bead s identifiedby acolorimetric assay,l86lhe agpeptidemolecule n the nterior:: nr bead s sequenced y Edmandegradation r by massspectrometry,[37]hich encodes:E iruc$re of the est compoundattachedo dle exterior of the bead,orher intercstingaltematives o molecular ag encodingare encodingby radiGftquency--,-:li:l anrl encodingwith apolymedcmatrix having unusualshapes.t8el ncodingmethods--t sorneday be displacedby massspectralanalyses, uch as maging time-of-flight sec-:.iir! ion massspectrometryTOF-SIMS).[9o]Mary huidleds of beads an be assayedn a:rngle measurementt the rate of about10 beads/sec, lthough here s aproblemwith ftag--nrarion of compounds,eading o a complicatedanalysis.Mass accuracy s about +0.01:-u. so n the 3.2 x 106-memberibrary of pentapptidestom 20 amino acids,all peptides,i\.epl rhosecontaining eucine and soleucine samemolecular weight), can be sepamted.B] incorpomtionof a ')N label nto either eucineor isoleucine,even hosepeptidescan be

d. NonpptideLlbr.rlca.t s discussedater n Section2.2.8.7,p.47,peptides onotmakevery usefuldmgs,espciallyif an orally activdrug is sought.TI| same echniques escribedabove or the s],nthesis fpeprideibrariescouldbe utilized to preparenonpeptideibaries; however, here s ar impor-unr differencebetweenhe chemistrywith pepiidesvqsus nonpeptides, amely, eactivity.In a rypical peptidecouplingreaction he carMiimide-activated N-protectedamino acidsare all about the same n reactivity with the different amino acids n the growing peptidechajn.Because f that, the split synthesismethodworkswell. However,with nonaminoacidreagents, uch asdifferent acid eblorides, he structureof th acid chlo.ide wil affect therarsof reactionwith differcnt nucleophiles.That could lead to mixores in which someofrhecomponents ave eactedandothershavenot. For each eaction he conditionshave o besorked out to be surecomplete eactionhasoccurred,Over thyeals t hasbeen ecognizedhat when argenumbersof nonpeptide nalogsarescreened imuttaneoudy,many aLsenegatiws (z\ activecompound hat doesnot prcducea l7't, .e.. a compoundhat showsa predeterminedevel of activity in the assay)and/akeportiv?s (an nactivecompoundhatgivesa hit) areobserved.A falsepositivemay arise roman mpurity n th sample estedor asarcsult of a complexbetvreenmorc han onecompound.Falsepositivesarc a wasteof time, but false negativesmean hatpotentialdrugs(or at leastlead compounds) re being overlooked. t is typical for pharmaceutical onPanies o canyour single entity screenso avoid theseploblems.Becauseof dis, individual compounds,rarher han mixtures,are synthesized.Nonetheless, ynthesison a solid supportalows thesFftesis of largenumt'rsof individual compounds pidly and obotically.The eactions recanied out ndividually in separatemiqotubes containing hepolymericsupport.This methodis referred o aspdrall"J s)rtherir rather hancombinatorialsynahesiscausehe ibrary ofcompounds in the range of 5G-ld compoundsn amouns of 1-5omg) is synthesizednparallelwithout combiningany of lhe tubs. Onestrategy hat can b used or potentiallymore effective ibraries s to selectprivilegedstructuresas he scatrold.Another strategy sio designa scaffold basedon an mportantmolecular cognitionmotif in the taryet eceptor.Th ibraries should ncorporatedifferentsetsof (commerciallyavailable)building blocks oproyidea large numberof diversesuuctures,and hey shouldcontain as much unctionalityaspossibleas recognitionelements.Moleculardiversity, however, s difficult to detetuine;Dixon andVillar have ound hai aproteir canbind asetof structurallydivene moleculeswith

41


36/37

chapler2 OrugDl5cov6ry ign'and Dwlopme

ScheBe 2.4 > Sotid-phasesynthesisof a nonpeptide ibrdy of privil'ged sitrctwes

,rmilarDoenlbindingaFfinttier'ul analog\ lo\el) relaledo lhese ompoundranexhibitvery ;at binding. ll Parallel'ynlhesis angeneraleman)morecompounocan canDe'rnlhesizedradilionally.nd heco't percompounds much o$erlo""; ; ; ; ; ; ; r ; ; ; t .pr idel ibra4otapr i ; i lesedstrucruIeIbenrodrazepinesr i ' 'hosninscheme .4.iqrlNole iat rhe rIslprece ftheben/odraleprne2'41ir notalrachedrrecll' otfr" ""i"*". f"tt".t",fttbolystirene. 2'49)' but is attached

o 2'46 insteado give 2'48 in avi l'"'"i,.o"or;n" tppr'.ia;etl1a-zodicarboxyate r DEAD) lf 2'47$ereartachedirecllyi;;;;;;l;;;;*. hindlance) fie potvmero rhe iIstchemicdreacrron a) re\ult''=., inliii'. .",,pir"g "l "n acrdchtoride

ortre ryt'rannanen hepterrnce r palladrumoene 2.50.To a'oid lharproblema 'pacergroup s typ'call' arLdchedo thepolymerwnlcn-rnoresthe 6rsr eactant way rom he pollmer 'o lhal slerichindrances nora proDremb"-p"".a ijf ""-"" * ttt" spu"e',*trictt *;tt r'' removedat the endof the svnthesis

nLhi'solid-oha,ernrle.i" Ulrce ivert^ elPn?n8can evaried:R' R) andRr'TheSrrlle:;;d';; J;;;. ;;"; .;r wiLhasman)acidchrorides' areavairabrero var) Rr Each"iii.'I-"o".,iijJo, .an becoupledio he'ameFmoc-prorecredminoacid luonde

n,rr. "."iI"por *.rt ol Lrte .50proJucrs anbe reated irh different moc-protected

mino".iJ nr"';ai', * ,r'r, , "ide lariei) of R2groups an be ncorpordted

cericacidcau'e'aurocvclrrationl 2.51 o 2.52 Again. ach 52 canbe realedwilh bd'eand he amearKyrn"irJi iitii.**i "r z.s2canie reated itha differentlkvlhalideosivea ibrary f2.53icteavaqerom he spacer ndpolymeresin ive'(he blar) of benTodiazepine'2 54r'lf 25ditre;t acidchlodde. ereusedn lheSlill couplingdndeach flhoseproducls a'rrealed ith25differenl mocprotecledmrno cid luoride\'heneach l tho\e ompounos"r-t"LiJ*i* z! aitr-*t alkvl halides, herewouldbe a ibrary of 25

x 25 x 25 or 15'625difierent benzodiazepinessingonly ?5 differentbuilding blocks'


37/37

f

lrs 2.2 Lesd Modlticatlon: uug ltellgn andOvolopmentDeipire the potential of combinatorial ibrary (or paralel) synthesis,natual productsle.r !o provide greaterstructual diversity than standardcombinatodal chemistry About!.i of ihe chemicalscaffoldsn the Dictionaryof Natural Productsand he BioactiveNatu-a Pirducts Databasea otal ofmorethan 100,000 ompounds) avenot been ynthesized.lF:Ih.rmore. naturalFoducts that are biologically active n assays enerallyhavedrug-like:-.rFrues. i.e., are capableof being absorbed nd metabolizede5lIsolatronof compounds-::! naturalsources nd rom combinatorialapproaches,owever, houldbecomplementary'

Sif,.rally the excessiveime taLeno isolateand chancterizebioactivecompoundstom nat-:-r1 prcductextraclss a disadvantage f themethod,but the ewardmaybegreatrmoleular::lelsrly, which gives he greatestopportunityto identify a variety of scaffolds or screen-ng. To attain a wide diversity of chemicalstructuresor screeningPulposes, omputationalrh:mists often reject compounds hat arc similar in structure;believirg that similar com-aJuds would havesimilar biological activities. n general,structurally similar compoundslr;\e similar biological activiiy. However, hebiological sinilarity rllay not be very srong;:i hasbenshown hat only 30%of compounds onsideredo be 8590sEuctually similar tor active compoundwil themselves ave he sameactivity.s] Addingjust one methyleneruup ro a 4-h)drorypiperidine-analoghangedL romapoorbinder f thechemokineecep-:. r CCR into apolenl inde."'l Thismaybebecauseimj arcompoundso nol necessarjlyiin{l ro the targei eceptor he sameway.Constructionof chemical ibraries basedon natual producthits is a sensiblecompro-ris approach.For example,Nicolaou and coworken developeda solid-phasemethod or'-:r prepararionf largenaturdl roducFlikeombinarorialibraries ased n lie pri! leged.ullcrurc .2-dimerhylbevoplran.61 scafloldound n many atural roducr\. heSeneralrerhodology is shown n Scheme .5. In this example he 2,2-dimethylbenzopymn caffold1i7) is generatedy reactionof the startingo-Fenyl phenol 2.55)with apolystyrerc-based.elenenyl bromideresin. A variety of reactionsarepossible o elaborate he side chains oiunher enbance he library (2.56).The 6nal productscan be released rom the polymericrupponby oxidation/elimination o 2.57. A library of morethan 10,000analogswas readilyprepared y this aPproach.

*-''z\--""'-'Y+ 'scheme 2.5 > Solid-pbaseynthesis f a natu.alprodDct-likeombinatorialibrary

O-**

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