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

jwcoe@pfizer.comjwcoe@pfizer.com

C. Everett Koop

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

19941994

N

HN

O

Laburnum anagyroidesGolden chain tree

Lupinus spp., Lupine

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

NH

N

N

VareniclineVarenicline

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%

N

N

H

nicotine

NH

NO

NH

NO

Br

NH

F

F

HN NHNH

R

NH

R

NH

N

NO O

N+NH

N