C‐10068: Novel Morphinan with a Unique Pharmacological Profile Philip Graham, PhD., Ara Aslanian PhD, Sophia Nguyen, Vinita Uttamsingh PhD, Adam Morgan PhD, Gary Bridson, LuAnn Sabounjian, James Shipley MD Concert Pharmaceuticals
§ Based on dextroETHorphan identified at NIH in 1990s (Tortella) – Evidence of anticonvulsant properties – Low oral bioavailability
– No human experience
§ C-10068 incorporates deuterium – Intrinsic pharmacology unchanged
– 3X increase in oral bioavailability (rat)
– Metabolite formation greatly reduced
§ Unique pharmacological profile – Acts at multiple targets
– Efficacy data in various preclinical models of seizure, pain and depression
§ Research collaborations with NINDS and WRAIR § Pre-IND development on-going
C-10068: Novel Anti-Epileptic Therapy
2
0 2 4 6 81
10
100
1000
C-10068dextroETHorphan
Time (hr)
Plas
ma
Con
cent
ratio
n (n
g/m
L)
NINDS: National Institute of Neurological Disorders and Stroke WRAIR: Walter Reed Army Institute of Research
C-10068: Efficacy in Models Conducted at NINDS
§ Maximal Electroshock Model ED50 ~ 20 mg/kg ip in mice and rats – Compared to dextromethorphan greater
potency, longer duration of action and wider therapeutic index
§ 6Hz Model – Partial protection
§ Formalin pain model in mice – 75% reduction in chronic/inflammatory
phase at 22 mg/kg (MES ED50) § Neuroprotection Assay (in vitro)
– Protects against NMDA and kainic acid induced neurotoxicity
3 Data generated by NINDS anti-convulsant screening program; Presented at Epilepsy Pipeline Meeting 2011
Rat MES
mg/kg (ip)
% r
ats
prot
ecte
d
0 10 20 30 40 50 60 700
20
40
60
80
100
C-10068DM
Formalin Paw Pain Model
Time (min)
Dur
atio
n of
paw
lick
ing
(s)
0 10 20 30 40 500
10
20
30
40
50C-10068Vehicle
22 mg/kg (ip)
C-10068 Binds to Pharmacologically Important Targets § Single-point (10µM) binding screen of 68 targets (Ricerca Lead Profiling screen) § Significant binding detected for potential target sites expressed in CNS
4
0
20
40
60
80
100
DM C-10068
Sigma-1 (h) NMDA (r) Na+ SERT (h) L-Type Ca2+ NET (h) Imidizoline I2 Channel (r) Channel (r) (r)
Bin
ding
at 1
0µM
(% In
hibi
tion)
CoNCERT Experiments 20190 and 20129
Binding to α1a, α2a, α2d adrenergic receptors detected, not shown.
>50% inhibition considered significant in this assay
C-10068 Exhibits More Potent Binding to Human Sigma Receptor than DM
5
-9 -8 -7 -6 -5 -40
20
40
60
80
100
120
DM
C-10068
Log Compound [M]
Sigm
a re
cept
orSp
ecifi
c bi
ndin
g (%
)
CoNCERT Experiment 20108
Human Jurkat cells, ligand: 8 nM [3H] pentazocine
Compound IC50, nM Ki, nM
C-10068 190 150 DM 1100 920
~6X
C-10068 Inhibits Serotonin Transport in Human Platelets
6
Compound IC50, nM
dextroETHorphan 201 C-10068 146
DX 2589
CoNCERT Experiment 20212
-10 -9 -8 -7 -6 -5 -4-25
0
25
50
75
100
125
C-10068dextroETHorphan
DX
Log Compound [M]
Sero
toni
n tr
ansp
ort
Inhi
bitio
n (%
)
Human platelets, [3H] 5-HT
§ C-10068 & dextroETHorphan inhibit serotonin transport more potently than dextrorphan (DX)
§ Recent studies1 suggest serotonergic agents may reduce risk of sudden death following seizure
1. Faingold C. Epilepsy & Behavior 22 (2011) 186–190 2. Bateman LM, Epilepsia. 2010 Oct;51(10):2211-4.
DX More Potent Inhibitor of rhNMDA Receptor Functional Activity than DM or C-10068
Cloned human NMDA receptors stably expressed in HEK293 cells analyzed by FLIPR
7
NMDA Receptor NR1/NR2A NMDA Receptor NR1/NR2B
CoNCERT Experiment 20219
-8 -7 -6 -5 -4 -3-50
0
50
100
150
200
DMC-10068
DX IC50 23.5µM
Log Compound [M]
NR
1/N
R2A
Inhi
bitio
n (%
)
-8 -7 -6 -5 -4 -3-50
0
50
100
150
200
DMC-10068
DX IC50 36.3µM
Log Compound [M]
NR
1/N
R2B
Inhi
bitio
n (%
)
DX is the only compound that had measurable IC50 in this assay
Human Liver Microsome Assay Demonstrates Dramatically Reduced Formation of Dextrorphan From C-10068 Versus DM
Compd ID Km µM
Vmax ng/min/mg
Vmax/Km mL/min/mg
Dextromethorphan DextroETHorphan C-10068
9.5 6.3
3.0
19.4 7.6
3.1
7.5 4.2
3.5
8
§ Contribution from structural change and incorporation of deuterium
§ Rate of formation (Vmax) of DX from C-10068~ 1/6th the rate at which DX is produced from DM
§ Efficiency (Vmax/Km) of formation of DX from C-10068 ~ 1/2 compared to DM
2.5 mg/mL HLM , 1-250 µM test articles, 30 min incubation, 0.3% organic
0 100 200 3000
5
10
15
20
25
DX from DMDX from dextroETHorphan
DX from C-10068
Conc (µM)
Dex
tror
phan
or D
-Dex
tror
phan
(ng
/min
/mg)
-‐0.5
0
0.5
1
1.5
2
# of NCS
/ 6 h block
Time
NCS Time Distribution Vehicle1mg/kg2.5mg/kg5mgk/g
C-10068 Studies at Walter Reed Army Institute of Research
§ Non-convulsive seizures (NCS) associated with poor prognosis following traumatic brain injury
§ Rat Model of Penetrating Ballistic-like Brain Injury (PBBI) – 30 minutes after injury groups of 16 rats treated with C-10068 at 1, 2.5 or 5 mg/
kg/h iv infusion or saline for 72 hours. – Continuous EEG monitoring - NCS start around 16 hours in about ¾ of animals
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* * *
*
C-10068 Infusion Dose-dependently Decrease NCS
§ Additional studies in progress at WRAIR – Histopathology from completed PBBI study – In vivo neuroprotection tests (catwalk, rotarod and Morris water maze)
at various timepoints following injury
/kg/hx72h /kg/hx72h
C-10068 Antidepressant Effect is Comparable to Imipramine Positive Control in Forced Swim Test Model
§ Drug administered ip 30 minutes before test § Time to first bout of latency for C-10068 also comparable to positive control § Potentially important attribute given co-morbidity of epilepsy and depression1
11
20 30 40 320
50
100
150
200
250 C10068
Dose mg/kg (ip)
Dur
atio
n of
Imm
obili
ty (s
)
Impiramine
1 Hoppe, C. & Elger, C. E. Nat. Rev. Neurol. 7, 462–472 (2011)
C-10068: Summary
§ Novel morphinan stabilized by incorporation of deuterium – Oral bioavailability increased by three-fold in rat – Reduced formation of undesired metabolite (dextrorphan)
§ Efficacious in various animal models – Maximal electroshock, 6Hz – Non-convulsive seizures following TBI – Inflammatory and neuropathic pain – Depression
§ Distinguishing characteristics – Unique pharmacological profile
§ Acts at multiple CNS targets – Protection against NMDA and kainic acid neurotoxicity (in vitro) – Potential antidepressant effect – Serotonergic properties may be protective against sudden death
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Acknowledgments
§ NINDS – Anticonvulsant Screening Program – James Stables PhD
– Tracey Chen PhD
– Jeff Jiang PhD
– H. Steve White PhD
§ WRAIR – Frank Tortella PhD
– May Lu, PhD
– Deborah Shear, PhD
– Major Kara Schmid
§ Chemistry – Adam Morgan, PhD
– Craig Masse, PhD
§ Bioanalytical – Changfu Cheng, PhD
– Gary Bridson
§ DMPK – Vinita Uttamsingh, PhD
– Richard Gallegos
– Sophia Nguyen
– Medicilon
§ Pharmacology – Ara Aslanian, PhD
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Philip Graham, Ph.D. [email protected]
Tel. 781-674-5246
