The Smoking Cessation Aid Varenicline (Chantix, Champix): Drug Discovery Inspired by Natural Products

Tobacco use remains the single largest preventable cause of morbidity in the United States, with approximately 440,000 premature deaths each year from smoking-related illnesses, such as cardiovascular disease, multiple types of cancer and pulmonary disease. The search for medications to assist people with their quit attempts has led to the introduction of three FDA approved first-line medications: 'safe' nicotine (Nicotine Replacement Therapy) in 1984, the antidepressant bupropion (Zyban) in 1997, and the α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline (Chantix, Champix) in 2006.

Varenicline was specifically designed to interact with α4β2 nAChRs, a subtype that plays a key role in the addictive properties of nicotine. The rationale was that a partial agonist would not only have a 'mild' nicotine-like action without abuse liability and reduce craving during abstinence, but with higher affinity for α4β2 nAChRs than nicotine it would also prevent nicotine's access to these receptors and thus reduce the nicotine reward when smoking during a relapse. This dual action was expected to improve clinical efficacy compared to existing treatments.

Pfizer started a discovery program in 1992 with a limited high-throughput screening effort, as the lack of understanding of the structural requirements for nAChR partial agonism prevented a 'de novo' design. At the same time chemistry efforts focused on natural products as a source for drug leads, given the abundance of nicotinic compounds in nature. Based on preliminary studies with anabaseine, anabasine, cytisine and lobeline, the rigid alkaloid cytisine was selected as a starting point. Cytisine, which is used in East-European countries for smoking cessation, is an α4β2 nAChR partial agonist with very poor brain penetration. The aim of making cytisine derivatives and analogs was to maintain a partial agonist profile, increase selectivity and to substantially improve its pharmacokinetic properties. When these efforts failed, because the cytisine derivatives were either antagonists, or had poor brain penetration, or had genetic toxicology findings, the lessons learned were applied to a novel scaffold, based on structural elements of another natural product, morphine. The recognition that an opioid derivative, which was reported in 1979 to lack analgesic properties, had the same bicyclic skeleton as cytisine and could have nicotinic properties, was a breakthrough that ultimately led to the synthesis of varenicline in 1997. It was quickly identified as a candidate with the desired properties: selective and high affinity for the target α4β2 nAChR, low efficacy partial agonism, excellent pharmacokinetic properties and efficacy in preclinical in vivo rodent models of dopamine reward and nicotine addiction. The compound was nominated for development in 1998 and after toxicological and phase 1 studies subsequent phase 2 and 3 trials demonstrated its efficacy and safety in adult smokers. The FDA and EMA approved varenicline as a smoking cessation aid in 2006.

Varenicline is the first nicotinic cholinergic drug to be marketed since mecamylamine in the 1950 s and has stimulated research on the one hand on potential therapeutic benefits of α4β2 ligands for other indications (alcoholism, depression, cognition), on the other hand on other nAChRs that may play a role in nicotine addiction. Interestingly, some novel compounds that are in the preclinical stage and target α3β4 nAChRs, are also based on a natural product, ibogaine. This presentation will focus on the synthesis and discovery of varenicline, summarize its pharmacology and clinical efficacy and briefly discuss recent developments in the search for nAChR ligands as therapeutics.