Rimonabant

Rimonabant (also known as SR141716; trade names Acomplia, Bethin, Monaslim, Remonabent, Riobant,  Slimona, Rimoslim, Zimulti, and Riomont) is an anorectic antiobesity drug that has been withdrawn from the market. It is an inverse agonist for the cannabinoid receptor CB1. Its main effect is reduction in appetite.

Rimonabant was the first selective CB1 receptor blocker to be approved for use anywhere in the world. In Europe, it was indicated for use in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m², or patients with a BMI greater than 27 kg/m² with associated risk factors, such as type 2 diabetes or dyslipidaemia. In the UK, it was available beginning in July 2006. As of 2008, the drug was available in 56 countries. On 23 October 2008, the European Medicines Agency (EMEA) issued a press release stating its Committee for Medical Products for Human Use (CHMP) had concluded the benefits of Acomplia no longer outweighed its risks, and subsequently recommended the product be suspended from the UK market. Sanofi-Aventis later released a press statement stating the drug had been suspended. Approval of the drug was officially withdrawn by the EMEA on 16 January 2009.

History
Despite the FDA's issuing an approvable letter in February 2006 for the obesity indication, and a nonapprovable letter for smoking cessation, the drug did not enter the market in the United States in 2006. The French pharma firm Sanofi-Aventis disclosed a complete response to the FDA's approvable letter was submitted on 26 October 2006, triggering a Class I (two-month) or Class II (six-month) review process. On 13 June 2007, FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval. Subsequently, Sanofi-Aventis announced it was suspending the new drug application (NDA) for rimonabant, and that it would resubmit an application at some point in the future.

On 21 June 2006, the European Commission approved the sale of rimonabant in the then-25-member European Union. Sanofi announced the first country in which Acomplia would be sold was the United Kingdom as a prescription drug. Sales began in July 2006. Sanofi also announced it projected that the drug would be sold shortly thereafter in Denmark, Ireland, Germany, Finland, and Norway. It was expected in Belgium and Sweden in 2007. Ordinary obesity would, according to official medical recommendations, not be enough to acquire the prescription in Sweden; there would be additional requirements concerning abnormal blood lipid levels.

The EU's approval was not a blanket approval, nor did it approve Acomplia for nonobesity-related problems, such as smoking cessation, although off-label use of the drug was still possible. The approval was, in combination with diet and exercise, for the treatment of obese patients (BMI greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.

In October 2008, the European Medicines Agency recommended doctors not prescribe the drug due to the risk of serious psychiatric problems and even suicide. The drug was subsequently suspended.

Side effects
Shortly after market introduction, press reports and independent studies suggested side effects occurred more intensely and more commonly than shown by the manufacturer in their clinical studies. Resulting from drug actions at CB1 receptors in the brain, reports of severe depression and suicidal thoughts are frequent. As CB1 receptors are fairly ubiquitous throughout the central nervous system, it is not currently understood where exactly the inverse agonist is acting to cause these side-effects.

On 15 June 2007, BBC News reported a committee advising the U.S. FDA had voted not to recommend the drug's approval because of concerns over suicidality, depression, and other related side effects associated with use of the drug.

Smoking cessation
Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi-Aventis is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapy. The Studies with Rimonabant and Tobacco Use (STRATUS) program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi-Aventis that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy. According to a Cochrane review in 2007, rimonabant "may increase the odds of quitting approximately 1 1/2 -fold".

Addiction
Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans: priming and cues. It may also reduce ethanol- and opiate-seeking behavior.

Memory
Tetrahydrocannabinol (THC) is known to impair short-term memory. It was therefore hypothesised that rimonabant may improve short-term memory. Indeed, in animal studies, it significantly improved the performance of rats to encode information in the short-term memory.

Blockage of cannabis effects
Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9-tetrahydrocannabinol (THC) in humans without affecting the pharmacokinetics.

Effect on physical activity
Rimonabant reduces voluntary wheel running in laboratory mice.

Effect on male fertility
Rimonabant significantly increased human sperm motility and viability in vitro.

Reaction
Rimonabant can be synthesized as follows: