Selective Dopamine D3/D2
Receptor Antagonist
PF-04363467
Travis Wager on behalf of the D3 GPCR Team
6th RSC / SCI symposium on GPCRs in Medicinal
Chemistry
Day 2 - Tuesday 14th June, 13:50
Aptuit, Verona, Italy
D3 Antagonists Work By Reducing Aberrant Reward And
Could Impact Many Diseases
So Why Opioid Addiction?
Reward response to stimuli
Disease
Population
R
e
w Aberrant reward
a
function
r
d
Normal
D3/D2
treatment in
Disease
Population
Reward response
V
a
l
u
e
•
More Americans now die every year from
drug overdoses than they do from motor
vehicle crashes
•
Over the last decade, opioid consumption has
increased nearly 500%, overdoses quadrupled
and death increased over 4% leading CDC to
place opioid addiction on the top-five public
health challenges to address
https://www.whitehouse.gov/the-pressoffice/2015/10/21
Case Study
Stimulus
Stimulus
Stimulus
The abnormal response (aberrant reward function) to stimuli
or cues translates as a disease.
Examples:
Opioids → opioid addicts
Cigarettes → smokers
Food → obese
Hand washing → OCD
Shopping → compulsive shoppers
112 opioid dependent veterans
78% completed detoxification and
referred to Intensive Outpatient
Program (49% naltrexone, 76%
aftercare plan)
22% completed 90 days of treatment
3% were abstinent from opioids at 90
days
1 year follow up: 4.5% had died
Davison et al. J Addict Disorders 2006
Pfizer Confidential │ 2
There is an Urgent Need for Better Treatments
for Substance Use Disorders
Prioritized Substance Use Disorders
G7 Prevalence /Treatment
 Substance Use Disorders are a major
contributor to global societal burden
 $560B in annual costs for health, welfare
and lost productivity in US alone
 > 200M people with tobacco, alcohol, or
opioid use disorders in G7
• Few seek treatment from HCPs;
consequences of use accelerates
presentation / treatment rates (e.g.
overdose/DUI, legal).
• High relapse rate: ~ 80% within first year
Tobacco
142M
Alcohol
59M
Opioids
5.4M
Prevalence
Few patients achieve long-term abstinence (> 1 y) with existing treatments.
Abstinence rates: Smoking cessation (22%), Alcohol (20%) and Opioid (13%)
Source: Decision Resources Epi-Database, WHO, Lancet
Note: OTC and Rx treatment can be +/- HCP recommended psychosocial interventions
What’s new and interesting: D3 or D3 preferring D3/D2
Partial Agonists or Antagonists
BioProjet 1.4979
D3 Ki: 0.3 nM (partial agonist)
D2 Ki: 957 nM (2737x)
Dofet. IC50: 6.9 uM (~1000x)
Signal of efficacy in Phase Ib
(10 patients, heavy smokers)
Phase II POC study in smoking cessation was complete in Oct.
2014. Results are unknown.
LD
CS
Preclinical
Phase I
Phase II
Phase III
Market
GSK598809 (Development Halted)
D3 Ki: 2.4 nM
D2 Ki: 3189 nM (3148x)
HLM: 38
MDR: 2.8
RRCK: 8
hERG IC50: 1.2 uM
Signal of efficacy in smoking population
(Psychometric signal)
4
Corporate file mining leads and tool compound
Compound
D3
Ki ( nM)a
D2
Ki ( nM)b
D2/D3
D3 Functional Ki
(nM)c
1e
20.1
1600
84
Antagonist
2f
3
679
3
>5000
428
>7
143
Agonist
1.3
Functional Activity
Antagonist
Selectivity and ADME Properties of PF-04363467
10% at 10 uM
HLM
Papp
NIH
P-gp
mBcrp
Rat AUC0-∞
Cb,u/Cp,u
PF04363467
126
8.4
6.6
2.4
1.01
100% at 10 uM
4 nM
ALPHA2A
CHT1
Ca Chan
5HT2B
Na Chan
M5
ALPHA2B
M1
M3
LTB4 BLT1
SIGMA
M4
ALPHA2C
CYP2C9
5HT1A
5HT2A
D1
H3
CYP3A4b
CYP3A4
5HT2A
5HT6
D2S
D2
CYP2C19
D3
7600 nM
Compound
• Highly selective D3/D2 antagonist
• Need to reduce Cyp2C19 inhibition
Figure 3: Human in vivo data vs NIH MDR efflux ratio
• Free brain drug levels are unity with
the plasma compartment
• Human CSF levels are predicted to
be high.
D3R and D2R brain receptor occupancy from
autoradiography techniques in rats
A)
B)
Ex-Vivo, D3 Receptor Occupancy
Ex-Vivo, D2 Receptor Occupancy
100
80
60
40
20
0
Dose = 0.1
-13
10
-12
10
3.2
-11
-10
10
PF-04363467
80
60
40
15
7
0
Dose = 0.01 0.032 0.1
32 mg/kg
-9
10
10
10
Free Brain Concentration (nM)
Compound
100
96
-8
10
-12
-7
10
10
-10
-8
10
10
Free Brain Concentration (nM)
32 mg/kg
D3 EVRO % RO
Observeda
---
D2 EVRO % RO
Observedb
85.9 ± 1.7
10 mg/kg
98.8 ± 2.4
50.6 ± 3.5
3.2 mg/kg
99.9 ± 0.5
34.7 ± 1.5
0.1 mg/kg
33.6 ± 4.5
10.8 ± 4.1
0.03 mg/kg
6.3 ± 10.1
---
EC50
1.5 ± 0.4 nM
46.6 ± 9.1 nM
D50
0.7 mg/kg
7.2 mg/kg
Treatment
3.2
10 mg/kg
-6
10
Nicotine Cessation
Pfizer D3 Antagonist Shows Similar Reduction in Nicotine Intake to Chantix
Drug Seeking Model
‘467 Dose
3.2
10
32
D3 RO %
100
99
ND
Measured D2 RO %
35
58
86
*
**
Pfizer Confidential │ 8
Opioid Relapse
Pfizer D3 Antagonist Reduces Opioid Relapse in Response to Drug-paired Cues
Drug Seeking Model
A)
# I n f u s io n s ( M e a n + S E M )
30
25
20
15
Extinction
Vehicle
3, 3.2 mg/kg
3, 10 mg/kg
3, 32 mg/kg
10
***
5
***
***
‘467 Dose
3.2
10
32
D3 RO %
100
99
ND
Measured D2 RO %
35
58
86
n
F
en
ta
n
ta
en
D
yl
yl
3
F
Treatment
ay
2
ay
D
D
ay
1
yl
n
ta
en
F
F
en
ta
n
yl
0
But….D2 are know to cause
sedation and unwanted
extrapyramidal symptoms (EPS)
PF-04363467 does not produce catalepsy and does not
affect spontaneous locomotor activity at doses tested
Catalepsy Experiment (20 sec cutoff criteria)
‘467 Dose
3.2
10
32
D3 RO %
100
99
ND
Measured D2 RO %
35
58
86
Titrating in D2 at levels required for improved efficacy does not produce catalepsy or
reductions in locomotor activity.
10
Early Efforts to Understand PF-04363467 Binding
Two sulfonamide binding modes proposed based on SAR, mutagenesis and modeling
o Proposed binding modes interact with conserved Asp110 through the basic
nitrogen of the morpholine or the sulfonamide NH
o Secondary binding pocket is better filled by the morpholine binding mode
o Orthosteric pocket is better filled by the sulfonamide binding mode
PF-04363467
PF-04363467
Morpholine-D110 interaction
Sulfonamide-D110 interaction
A)
B)
SBP
TM7
Glu90
Ile183
TM2
TM6
TM2
TM6
TM7
Tyr36
Tyr36
TM5
OBS
Asp110
TM4
TM3
TM5
Tyr373
TM1
OBS
Asp110
Tyr373
TM1
TM4
TM3
Eticlopride (literature xray structure) in gray
Prospective In silico prediction of 476 binding mode
A collaboration between Neuroscience Medicinal Chemistry and Acellera
1
2
D110
3
4
F197
5
Anabella Villalobos
Noelia Ferruz & Simone Sciabola
Physicochemical properties and
CNS MPO desirability
CNS MPO Desirability
Compound 1
Alignment of ADME attributes
Compound 2
Compound 3
Property
Value
Component
Score
Value
Component
Score
Value
Component
Score
MW
402
0.70
235
1.00
403
0.70
ClogP
4.46
0.27
1.48
1.00
4.06
0.47
TPSA
67.4
1.00
51.4
1.00
58.6
1.00
ClogD7.4
1.06
1.00
0.76
1.00
3.96
0.02
HBD
2
0.50
2
0.50
1
0.83
pKa
10.6
0.00
7.5
1.00
7.5
1.00
CNS MPO
aCalculated
3.5/ 6.0
5.5/ 6.0
4.0/ 6.0
CNS MPO desirability scores were obtained using the published algorithm.
Wager, T. T., Hou, X., Verhoest, P. R., and Villalobos A.
ACS Chem. Neurosci. 1, 435-449, 2010.
Summary of PF-04363467
Medicinal Chemistry Parameters
Modeled binding to D3 based on
MD simulations
LipE
4.6
LE
0.3
CNS MPO
4.0
cLogP
4.1
cLogD
3.9
pKa
7.5
GPCR activity (nM)
Novel induced binding pocket
PK
D3 antagonist
3.0
NIH MDR AB/AB
6.6
D2 antagonist
428
RRCK AB
8.4
D2/D3
143x
HLM
120
5HT6
900
Cyp2C19
110 nM
5-HT1A partial agonist
1100
Rat AUC0-∞ Cb,u/Cp,u
1.0
5HT2A, 1400 nM
1400
hERG = 1.7 uM




PF-04363467 is a potent brain penetrant selective D3/D2 compound.
Efficacy in rodent models of addiction require some D2 activity
No EPS liabilities observed with selective D3/D2 antagonist PF-04363467 at high D2 RO
High HLM clearance precludes clinical development of PF-04363467
 CNS MPO suggests lowering ClogD with improve ADME and Safety attributes
Pfizer Confidential │
14
Acknowledgements
Chemistry
Structure Biology
PPG
Biology
Bethany Kormos
Simone Sciabola
Xinjun Hou
Natasha Kablaoui
Jaclyn Henderson
Noelia Ferruz
Nandini Patel
Jamie Tuttle
Patrick Verhoest
Travis Wager
Joe Young
Joe Tucker
Rama Chandrasekaran
Thomas Knauber
Karen Coffman
Tom Chappie
Robin Nelson
Matt Griffor
Eric Marr
Xiaomin Chen
Yaozhong Zou
Xiayang Qiu
Michelle Vanase-Frawley
Claire Steppan
Rebecca O’Connor
Andy Mead
Liz Dunn-Sims
Jamie DaSilva
Mark Majchrzak
Keith Dlugolenski
Chris Schmidt
Nancy Stratman
Corey Puryear
David Horton
Patricio O’Donnell
PDM
Aarti Sawant-Basak
Christine Orozco
Safety
Jessica Whritenour
Gary Freeman
Pharm Sci
Suman Luthra
Amber Haugeto
Clinical
Chris Chatham
Brendon Binneman
Danny Chen
Renee Heese
David Nguyen
15