Design Of An Antismoking Pill
Design Of An Antismoking Pill
The makers of varenicline got their inspiration from two natural products
AMANDA YARNELL
More than two-thirds of the U.S.'s nearly 50 million smokers want to quit
smoking-but only about 5% of those who try actually manage to kick the habit
cold turkey, according to estimates from the Centers for Disease Control &
Prevention. Pfizer is hoping that varenicline, a smoking-cessation agent now in
late-stage Phase III clinical trials, could improve quitters' chances.
If approved, varenicline will join a market for smoking-cessation drugs that's
currently dominated by nicotine replacement therapy. Patches, gums, nasal
sprays, and inhalers help lessen smokers' cravings to light up by providing low
levels of nicotine, the addictive ingredient in tobacco. The only nonnicotine
antismoking medication currently on the market is GlaxoSmithKline's Zyban, a
drug originally used to treat depression.
Varenicline, in contrast, "is the first nonnicotine antismoking medicine
designed specifically to help smokers stop smoking," notes Jotham W. Coe, a
research fellow at Pfizer. His team recently detailed the chemical logic behind
the development of this molecule (J. Med. Chem. 2005, 48, 3474).
ADDITION TO nicotine is thought to stem from the molecule's ability to bind to a
class of ion channels in the central nervous system. Called neuronal nicotinic
acetylcholine receptors (nAChRs), these channels normally bind the messenger
molecule acetylcholine. Nicotinic acetylcholine receptors in the part of the
brain that responds to pleasurable or "reinforcing" stimuli-for instance, food,
sex, drugs, or gambling-trigger the release of dopamine, a neurotransmitter
associated with addiction.
Nicotine binds these same receptors to trigger dopamine release. Once smokers
become dependent on the modest but pleasurable bursts of dopamine that accompany
each drag on a cigarette, quitting smoking can be difficult.
"What we were after was a dopamine 'nightlight' that would be on at a low level
until the smoker quit," Coe says. He and Pfizer chemists Eric P. Arnold, Paige
R. Brooks, Michael G. Vetelino, and Brian T. O'Neill set about designing a
molecule that would partially activate a particularly abundant nAChR subtype
called 42. Like nicotine replacement therapies, such a molecule would reduce
cravings and withdrawal symptoms by causing the release of a constant low level
of dopamine, Coe says. "But importantly, we also wanted the molecule to block
nicotine from binding" so that smokers wouldn't get any satisfaction from
lighting up, he adds.
The Pfizer team first searched for compounds that might partially mimic
nicotine's ability to activate 42. Their hunt turned up (-)-cytisine, a bicyclic
plant alkaloid. A Bulgarian pharmaceutical company currently markets cytisine
for smoking cessation. The drug has met with little success, however, presumably
because it suffers from poor absorption and brain penetration properties, Coe
hypothesizes.
In hopes of improving upon cytisine, the Pfizer researchers, led by O'Neill,
devised a pair of practical synthetic routes to the alkaloid for medicinal
chemistry studies (Org. Lett. 2000, 2, 4201 and 4205). They experimented with
various derivatives, but these proved unworkable. Things began to look gloomy,
until Coe-who had worked on morphine chemistry before joining Pfizer-made a
pivotal observation.
Coe recognized that cytisine's structure is similar to that of the significantly
larger alkaloid morphine, notes Craig A. Townsend, an organic chemistry
professor at Johns Hopkins University. The two molecules' [3.3.1] bicyclic
skeletons differ only by the position of a single nitrogen atom.
Organic chemists have spent lots of time and energy simplifying morphine while
retaining the activity in the simplified versions, Townsend notes. Coe's team
cleverly used this information to guide their attempts to simplify cytisine
while maintaining its activity, Townsend points out. The result was a [3.2.1]
bicyclic benzazapine that potently blocks nicotine binding to 42. Unfortunately,
however, this simplified molecule lacks cytisine's ability to partially activate
42 and release low levels of dopamine. The team serendipitously restored this
property by fusing heterocycles onto the benzazapine's aromatic ring via an
unexpectedly regioselective dinitration reaction.
One derivative, dubbed varenicline, has the best of both worlds: It partially
activates 42 "to give some dopamine release so the person won't have so much
craving," notes Susan Wonnacott, a neuroscience professor at the University of
Bath, in England. "But at the same time, varenicline prevents nicotine from
exerting any effect by blocking nicotine's access to these receptors," she adds.
The oral drug is well-tolerated, Coe notes. In clinical trials, about half of
the smokers taking varenicline twice daily ceased smoking by the end of 12
weeks, compared with 12% of those on a placebo. These quit rates are roughly
double those reported for Zyban, Coe tells C&EN. Late-stage Phase III studies
now under way are examining whether varenicline helps smokers remain smoke-free
in the long term.
If approved, varenicline is likely to face some stiff competition as drugmakers
scramble to create products to help the world's 1.25 billion smokers kick the
habit. Last month, Sanofi-Aventis asked the Food & Drug Administration to
approve Acomplia for both obesity and smoking cessation. The drug, originally
designed to help people lose weight, also curbs nicotine cravings (and
presumably other types of cravings, too) by blocking the brain's endocannabinoid
reward system. In addition, Nabi Biopharmaceuticals, Rockville, Md., and
Zurich-based Cytos Biotechnology both have antinicotine vaccines in development.
These vaccines are intended to eliminate the pleasure of smoking by sopping up
the nicotine that smokers get from every drag, preventing it from ever reaching
the brain.
Chemical & Engineering News
ISSN 0009-2347
http://pubs.acs.org/cen/news/83/i23/8323antismoking.html