the science behind champix: from idea to tablet jotham w. coe and ivan efremov, phds department of...
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The Science behind Champix: The Science behind Champix: From Idea to TabletFrom Idea to Tablet
Jotham W. Coe and Ivan Efremov , PhDs Jotham W. Coe and Ivan Efremov , PhDs
Department of NeuroscienceDepartment of NeurosciencePfizer Global Research and DevelopmentPfizer Global Research and Development
Groton, CTGroton, CT
[email protected]@pfizer.com
Smoking is the Leading Cause of Preventable Death
Adapted from Mokdad AH et al. JAMA. 2004;291:1238-1245. CDC. MMWR. 2008;57:1226-1228.
Sexual Behavior (20,000)
Diet/Activity(400,000)
37.5%
Illicit Use of Drugs (17,000)
Motor Vehicles (43,000)
Firearms (29,000)
Toxic Agents (55,000)
Microbial Agents(75,000)Alcohol
(85,000)
Tobacco Use: (435,000 deaths of which 399,000 were related to smoking; the remainder to secondhand smoke and smokeless tobacco)
Preventable Causes of Death in the United States
3
Ischemic Heart Disease Stroke – Vascular Dementia Peripheral Vascular Disease Abdominal Aortic Aneurysm
Cardiovascular
Adverse Surgical Outcomes/Wound Healing Hip Fractures Low Bone Density Cataract and Macular Degeneration Peptic Ulcer Disease Metabolic Syndrome
Other
Lung Oral Cavity/Pharynx Laryngeal Esophageal Stomach Pancreatic Kidney Bladder Cervical Leukemia
Cancer COPD Community-acquired
Pneumonia Poor Asthma Control
Respiratory
Erectile Dysfunction Reduced Fertility Pregnancy Complications Low Birthweight SIDS
Reproductive
Adapted from CDC Surgeon General’s Report 2004
Smoking is a Risk Factor Across an Array of Diseases
Adapted from CDC. Surgeon General’s Report. 2004.Weitzman M et al. Circulation. 2005;112:862-869. 4
Active Smoking
Nicotine Addiction: Nicotine Addiction: Reinforcing BehaviorReinforcing Behavior
Nicotine binds Nicotine binds predominantly predominantly to nicotinic to nicotinic acetylcholine acetylcholine (nACh) receptors (nACh) receptors in the CNS; the in the CNS; the primary is the primary is the 442 nicotinic 2 nicotinic receptor in receptor in the Ventral the Ventral Tegmental Tegmental Area (VTA)Area (VTA)
Binding of nicotine to the Binding of nicotine to the 442 nicotinic receptor in the VTA results 2 nicotinic receptor in the VTA results in a release of dopamine in the Nucleus Accumbuns (nAcc) which is believed in a release of dopamine in the Nucleus Accumbuns (nAcc) which is believed to be linked to rewardto be linked to reward
4 2224
42Nicotinic Receptor
Mechanism of Action of Nicotine Mechanism of Action of Nicotine in the Central Nervous Systemin the Central Nervous System
Roller coaster of dopamine signals, self-regulated by the smokerRoller coaster of dopamine signals, self-regulated by the smoker
4 2224
42Nicotinic Receptor
Smokers make multiple quit attempts,Smokers make multiple quit attempts,but failure is the norm: Nicotine is addictive!but failure is the norm: Nicotine is addictive!
Total Smokers – 51 M
Actually quit ~ 1 Million (2%)
Want to Quit – 36 M
Try to Quit -23 M
Sources: WHO http://www1.worldbank.org/tobacco/index.htm; US National Health Interview Survey,1995
70%
45%
4% of those who try
Withdrawal Symptoms from Stopping Smoking
Withdrawal Symptoms from Stopping Smoking
0 1 2 3 4 5 6 7 8 9 10
Duration (weeks) or more
Jarvis MJ. BMJ 2004;328:277-279.
Incidence
Increased appetite
Restlessness
Depression
Irritability/aggression
Craving for nicotine
Poor concentration
Sleep disturbance
Lightheadedness
70%
60%
60%
50%
70%
60%
25%
10%
Nicotine Delivery by Cigarettes and Nicotine Delivery by Cigarettes and Nicotine Replacement Therapy (NRT)Nicotine Replacement Therapy (NRT)
Adapted from 1. Benowitz NL et al. Clin Pharmacol Ther. 1988;44:23-28; 2. Schneider NG et al. Clin Pharmacokinet.1996;31:65-80; 3. Benowitz NL. Drugs. 1993;45:157-170.
NRT has rates of delivery which are all less than that of cigarette smoking NRT acts as an agonist alone, mimicking nicotine in its mechanism of action Peak levels achieved by NRT are about 30-50% of those achieved by smoking
Cigarette (nicotine delivery, 1-2 mg)Gum (nicotine delivery, 4 mg)Nasal spray (nicotine delivery, 1 mg)Transdermal patch (nicotine delivery, 15-21 mg)
Time Post-administration (minutes)
Pla
sma
Nic
otin
e C
once
ntra
tion
(μg/
L)
0
2
4
6
8
10
12
14
16
18
-10 0 10 20 30 40 50 60 70 80 90 100 110 120
Hypothetical Effects on Mesolimbic DA Release Hypothetical Effects on Mesolimbic DA Release of Smoking and Smoking with Nicotine of Smoking and Smoking with Nicotine Replacement Therapy (NRT) or Partial AgonistReplacement Therapy (NRT) or Partial Agonist
Time
Responseto nicotine
Smoking NRT + smoking Partial agonist + smoking
Rationale for Rationale for 442 nAChR Partial Agonists2 nAChR Partial Agonists
Nicotine Part Ag Part ag
442 nAChR2 nAChR
Dual action of a partial agonistDual action of a partial agonistDual action of a partial agonistDual action of a partial agonist
Agonist
ResponseResponse100%100%
Nicotine
SmokingSmokingNo Partial AgNo Partial Ag
SmokingSmokingNo Partial AgNo Partial Ag
No SmokingNo SmokingPartial AgPartial Ag
No SmokingNo SmokingPartial AgPartial Ag
SmokingSmoking+ Partial Ag+ Partial Ag
SmokingSmoking+ Partial Ag+ Partial Ag
Antagonist
50%50%Potential to block Potential to block reinforcing effectsreinforcing effectswhen smokingwhen smoking
Potential to block Potential to block reinforcing effectsreinforcing effectswhen smokingwhen smoking
Partial Agonist
50%50%Potential to relieve
craving and withdrawalwhen quitting
Potential to relievecraving and withdrawal
when quitting
N
O
N
R
Y
X
R Decreased Binding Me, Bn, Allyl, SO2CF3, etc.
Y Decreased Binding E+, Me, Bn, Allyl, Aryl, etc.
X Br, Cl, Me, Ac, Aryl, OR etc
Potent h Binding (0.2 nm)Selective (>100x)Partial Agonist, in vitro56% PA, DATO (0.05 mg/kg, p.o.)Self Admin and Discrimination
$1700/g!!
plant sourcesgeneticsynthetic . . .
Bromo-Cytisine
100
110
120
130
140
150
160
170
180
0.001 0.01 0.1 1 10 17.8
DOSE, mg/kg, s.c.
Nicotine
Cytisine Alone
Cytisine w / Nicotine
Br-Cytisine Alone
Br-Cytisine w/ Nicotine
Dopamine Turnover in Rat Nucleus Accumbens.
**
++ **
** **
Nicotine @ 1mg/kg, s.c.
+ ** **
**
**
+ p<.05 vs nicotine ** p<.01 vs vehicle
Cytisine Total SynthesisIntramolecular Heck Route
N
O
HO OH
N
O
HN
N
O
O
N
O
N
O
MnO2,
benzene
20% overall
OMs
Alkylationt-BuOK, THF
cat. n-Bu4NIDMF
1) LiHMDS, THF O °C - rt, 1/2 h2) ClP(O)(OEt)2 -78 °C - rt 1.5 h
3) 2% Pd(OAc)2 4% POT, TEA CH3CN, 60 °C 18 h, 53 - 57%
NaIO4EtOH, H2O
then NH4OHH2, Pd(OH)2
Me3NO•2H2Ocat. OsO4
CH2Cl2
77% 85% 58%
91%
Org. Lett. 2000, 2, 4205 also 4201
NBSCH2Cl2
quant
Synthesis: Clues from NatureSynthesis: Clues from Nature
Cytisine
N
HN
OOH
N
O
OHMorphine
N
N
H
Nicotine
HN
Tobacco plant Golden Chain Opium poppy
HN
HN
HN
CP-526,555Varenicline
ChantixChampix
HN
N N
RN
O2N NO2
Minor side product
42 nAChRantagonist
HN
O2N
42 nAChRpartial agonist
Nicotinic Receptor Binding Affinities (nM)Nicotinic Receptor Binding Affinities (nM)
42
34
7
1
hdiffraction
NH
N
N
34% agonist66% antagonist
vehicle nicotine Varenicline 5.6 mg/kg,s.c.
vehicle
w/ Nicotine 1 mg/kg,s.c.
Dopamine Turnover in Rat NucleusAccumbens
++ p ,.01 vs nicotine
0
20
40
60
80
100
++
DO
PA
C+
HV
A/D
A,
% N
ico
tin
e
NH
N
N
75
100
125
150
175
200
-180 -120 -60 0 60 120 180 240 300 360
Time (minutes)
Do
pa
min
e R
ele
as
e i
n N
. A
cc
um
be
ns
% o
f B
as
al
± S
EM
Nicotine 0.32 mg/kg sc
Varenicline 1 mg/kg po+ Nicotine 0.32 mg/kg sc
Varenicline 1 mg/kg po
Nicotine 0.32 mg/kgVarenicline 1 mg/kg po
Partial Agonist Effect on Dopamine ReleasePartial Agonist Effect on Dopamine Releasein Rat Nucleus Accumbensin Rat Nucleus Accumbens
75
100
125
150
175
200
-180 -120 -60 0 60 120 180 240 300 360
Time (minutes)
Dop
am
ine R
ele
ase in
N.
Accu
mb
en
s%
of
Basal ±
SEM
Nicotine 0.32 mg/kg sc
Varenicline 1 mg/kg po+ Nicotine 0.32 mg/kg sc
Antagonist Effect on Dopamine ReleaseAntagonist Effect on Dopamine Releasein Rat Nucleus Accumbensin Rat Nucleus Accumbens
Nicotine 0.32 mg/kgVarenicline 1 mg/kg po
AAbsorptionbsorptionSmall (MW=211), very water solubleSmall (MW=211), very water solubleGood membrane penetration (passive diffusion), highly absorbedGood membrane penetration (passive diffusion), highly absorbed99% of recovered 99% of recovered 1414CC material excreted in urinematerial excreted in urineNot a substrate for the P-glycoprotein efflux transporterNot a substrate for the P-glycoprotein efflux transporter
ADME properties in human
Distribution Low protein binding (fu 0.8) Moderate volume of distribution (1.9 L/kg)
Metabolism Excreted >90% as unchanged drug in the urine Minor hydroxy- and N-carbamoylglucuronide metabolites Parent drug represents 90% of circulating drug-related material Does not inhibit cytochrome P450 enzymes
Excretion Renal clearance (mainly passive diffusion): 2.4 mL/min/kg Long half life: T1/2 ~24 hr (accumulated data from multiple clinical
studies)
Drug Metabolism and Disposition 2006, 34, 121-30
Varenicline: Most Common Adverse EventsFrom 12-week Fixed-Dose, Placebo-Controlled Studies
Adverse EventVarenicline0.5 mg BID
n=129
Varenicline1 mg BID
n=821
Placebo
n=805
Nausea 16% 30% 10%
Insomnia * 19% 18% 13%
Abnormal Dreams 9% 13% 5%
Constipation 5% 8% 3%
Flatulence 9% 6% 3%
Vomiting 1% 5% 2%
* Includes Preferred Terms: Insomnia/Initial insomnia/Middle insomnia/Early morning awakeningAdverse events listed occurred in >5% and twice the rate seen in placebo-treated patients
Prescribing Information. Pfizer Inc, New York, NY. (May 2006)
Withdrawal Symptoms from Stopping Smoking
0 1 2 3 4 5 6 7 8 9 10
Duration (weeks) or more
Jarvis MJ. BMJ 2004;328:277-279.
Incidence
Increased appetite
Restlessness
Depression
Irritability/aggression
Craving for nicotine
Poor concentration
Sleep disturbance
Lightheadedness
70%
60%
60%
50%
70%
60%
25%
10%