1. The Science behind Champix: From Idea to Tablet Jotham W. Coe and Ivan Efremov, PhDs Department of Neuroscience Pfizer Global Research and Development Groton, CT jwcoe@pfizer.com

2. C. Everett Koop

3. 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

4. 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

5. Mortality in patients with coronary artery disease Weisman et al. Arch Intern Med 2002; 162: 2197-2202; LaRosa et al. JAMA 1999; 282: 2340-2346 Freemantle et al. BMJ 1999; 318: 1730-1737; Flather et al. Lancet 2000; 355: 1575-1581 Critchley & Capewell, JAMA 2003; 290: 86-97; Wilson et al., Arch Intern Med 2000; 160: 939-944 AspirinACE-I  blockers Statins Smoking cessation Reduction in mortality [%] 0 10 20 30 40

6. Nicotine Addiction: Reinforcing Behavior u Nicotine binds predominantly to nicotinic acetylcholine (nACh) receptors in the CNS; the primary is the  4  2 nicotinic receptor in the Ventral Tegmental Area (VTA) u Binding of nicotine to the  4  2 nicotinic receptor in the VTA results in a release of dopamine in the Nucleus Accumbuns (nAcc) which is believed to be linked to reward 44 22 22 22 44  4  2 Nicotinic Receptor

7. Mechanism of Action of Nicotine in the Central Nervous System u Roller coaster of dopamine signals, self-regulated by the smoker 44 22 22 22 44  4  2 Nicotinic Receptor

8. Smokers make multiple quit attempts, 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

9. Withdrawal Symptoms from Stopping Smoking 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% 50% 70% 60% 25% 10%

10. After inhalation, nicotine enters the brain in a matter of seconds and binds predominantly to the  4  2 subtype of neuronal Nicotinic Acetylcholine Receptors (nAChRs) Nucleus Accumbens LUNGS NICOTINE FROM SMOKING NICOTINE VTA Nicotine Addiction: Reinforcing Behavior

11. Nicotine Delivery by Cigarettes and 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

12. Hypothetical Effects on Mesolimbic DA Release of Smoking and Smoking with Nicotine Replacement Therapy (NRT) or Partial Agonist Time Response to nicotine Smoking NRT + smokingPartial agonist + smoking

13. Rationale for  4  2 nAChR Partial Agonists Nicotine Part Ag Part ag  4  2 nAChR Dual action of a partial agonist Agonist Response 100% Nicotine Smoking No Partial Ag No Smoking Partial Ag Smoking + Partial Ag Antagonist50% Potential to block reinforcing effects when smoking Partial Agonist50% Potential to relieve craving and withdrawal when quitting Potential to relieve craving and withdrawal when quitting

14. 1994

15. Laburnum anagyroides Golden chain tree Lupinus spp., Lupine

16. R Decreased Binding Me, Bn, Allyl, SO 2 CF 3, 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 vitro 56% PA, DATO (0.05 mg/kg, p.o.) Self Admin and Discrimination $1700/g!! plant sources genetic synthetic... Bromo-Cytisine

18. Cytisine Total Synthesis Intramolecular Heck Route Org. Lett. 2000, 2, 4205 also 4201

19. 1994 Cytisine Derivatives Studied

20. Synthesis: Clues from Nature Synthesis: Clues from Nature Cytisine Morphine Nicotine Tobacco plant Golden Chain Opium poppy

21. CP-526,555 Varenicline Chantix Champix Minor side product  4  2 nAChR antagonist  4  2 nAChR partial agonist

22. Varenicline

23. Nicotinic Receptor Binding Affinities (nM)  4  2  3  4  7  1      h diffraction NH N N

24. 34% agonist 66% antagonist vehiclenicotineVarenicline 5.6 mg/kg,s.c. vehicle w/ Nicotine 1 mg/kg,s.c. Dopamine Turnover in Rat Nucleus Accumbens ++ p,.01 vs nicotine 0 20 40 60 80 100 ++ DOPAC+HVA/DA, % Nicotine

25. 75 100 125 150 175 200 -180-120-60060120180240300360 Time (minutes) Dopamine Release in N. Accumbens % of Basal ± SEM 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/kg Varenicline 1 mg/kg po Partial Agonist Effect on Dopamine Release in Rat Nucleus Accumbens

26. 75 100 125 150 175 200 -180-120-60060120180240300360 Time (minutes) Dopamine Release in N. Accumbens % of Basal ± SEM Nicotine 0.32 mg/kg sc Varenicline 1 mg/kg po + Nicotine 0.32 mg/kg sc Antagonist Effect on Dopamine Release in Rat Nucleus Accumbens Nicotine 0.32 mg/kg Varenicline 1 mg/kg po

27.  A bsorption Small (MW=211), very water soluble Good membrane penetration (passive diffusion), highly absorbed 99% of recovered 14 C material excreted in urine Not a substrate for the P-glycoprotein efflux transporter ADME properties in human  D istribution Low protein binding (f u  0.8) Moderate volume of distribution (1.9 L/kg)  M etabolism 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  E xcretion Renal clearance (mainly passive diffusion): 2.4 mL/min/kg Long half life: T 1/2 ~24 hr (accumulated data from multiple clinical studies) Drug Metabolism and Disposition 2006, 34, 121-30

29. Varenicline: Most Common Adverse Events From 12-week Fixed-Dose, Placebo-Controlled Studies Adverse Event Varenicline 0.5 mg BID n=129 Varenicline 1 mg BID n=821 Placebo n=805 Nausea16%30%10% Insomnia * 19%18%13% Abnormal Dreams 9%13%5% Constipation5%8%3% Flatulence9%6%3% Vomiting1%5%2% * Includes Preferred Terms: Insomnia/Initial insomnia/Middle insomnia/Early morning awakening Adverse events listed occurred in >5% and twice the rate seen in placebo-treated patients Prescribing Information. Pfizer Inc, New York, NY. (May 2006)

30. Withdrawal Symptoms from Stopping Smoking 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% 50% 70% 60% 25% 10%