Post on 28-Dec-2015
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Discovering new drugs in Africa
Defeating Malaria Together
Kelly Chibale PhD FRSSAf
University of Cape Town
Drug Discovery: kissing many frogs before meeting the prince
Identify disease
Identify-validate target
Identify lead
molecules
Optimize lead
molecules
Pre-clinical trials
Clinical trials
Approval & marketing
Drug discovery process
New medicines - guided by structure
Genome:All drug
able targets
ValidateKnock-out organisms
Assay Set-up
Validation
HTSSpecific Target
Deng X et al, J Biol Chem. 284: 26999-7009 (2009)
Booker ML et al, J Biol Chem. in press(2010)
• Rapid progression with validated targets
New medicines: guided by Biology
Chemistry:All available molecules
HTSWhole parasite
Hits to leads
Identify resistance
• Screening five million compounds
• 25’000 hits < 1 uM
• Fast track to man – less than four years
• Bottle neck: how to optimise them for activity in patients
Gamo FJ, et al., Nature 465 (7296): 305–310 (2010) Guiguemde WA, et al., Nature 465, 311–315 (2010)Rottman M., et al, Science 325 1175-1180 (2010)Wells TNC Science 329 1153-1154 (2010)
Optimizing molecules to be medicinesData used to make additional refinements to the library Use data to refine compound
design using SARs
Example: Aminopyridines a new exciting anti-malarial series
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• In vivo P. berghei inhibition (p.o.) 99.5%, > 30 days survival with cures, including 30 mg/kg single dose cure.
• Cured all mice in onset and recrudescence assay. No recrudescence observed.
• ED90 (single dose, p.o.): 1.74 mg/kg
• T1/2 = 7-8 h; BA = 51%@ 20mg/kg 50 60
Pla
sma
Co
nce
ntr
atio
n (
µM)
Time (h)
Rat PK profiles for frontrunner after i.v. and p.o. dosing
10
1
0.1
0.01
10 20 30 400
N NH2
R2
R1
• Exciting new chemical series• Project led from H3-D (Cape Town) supported by TIA and MMV• Single dose cures in mouse models of malaria• Preclinical Candidate expected 1H 2012
Success built on the right chemistry
• New Hits to leads model pioneered by UCT and MMV
• Dedicated teams: medicinal chemists, cell pharmacology
• Partnered with South African Technology Innovation Agency
• MMV experienced Mentors
• Common in vivo centres of excellence
Natural Products: African solutions to a global disease
N
O
OH
N
H
O
O OO
O
H H
H
O
O OO
H H
HO
O
HO
O
NCl
HNN
Half life 8 h Half life 278 h
Insoluble Soluble half life <1h
Soluble half life >24h
O
OO
ONH
NH2R
• Clinically characterise products ‘active in man’
• Reconstruct what happens to natural products in the body
Natural products as starting points for future anti-malarial therapies: going back to our roots? Wells TN Malaria Journal 2011,10:S3. How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials? Guantai E, Chibale K Malaria Journal 10:S2
Understanding natural products and their metabolism
• Some molecules have to be metabolised to be active
• Study in vitro with enzymes to replace liver and gut
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(a)Electrochemical oxidation approach
(b)CYP450 oxidative metabolism: human & rat liver
microsomes, bactosomes and recombinant CYP450s
CYP1A1
CYP1A2
CYP2B6
CYP2C9
CYP2D6
CYP3A4
CYP2E1
CYP2A6
CYP2C19
Parent cpd metabolites
CYP1A1CYP2C9
In vitro In vitro Generation of MetabolitesGeneration of Metabolites
6.0 7.0 8.0 9.0Time, min
Inte
nsity, cp
s
DC13
21B3
9-10A
Human Liver Microsomes
DC13 + [O]
DC13 – [SIDE CHAIN]
Inte
nsity, cp
sIn
ten
sity, cps O O
MeO
OMe
O
Thanks to all our colleagues and partners – but especially to the children and their families who make the next
generation of malaria therapy a reality