Rimonabant
 |
|
|---|---|
| Systematic (IUPAC) name | |
| 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-N-(piperidin-1-yl)- 1H-pyrazole-3-carboxamide |
|
| Clinical data | |
| AHFS/Drugs.com | Consumer Drug Information |
| Licence data | EMA:Link |
| Pregnancy cat. | Not assigned, use not recommended |
| Legal status | Withdrawn from European market[1]; not approved elsewhere[2] |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | Undetermined |
| Protein binding | Nearly 100% |
| Metabolism | Hepatic, CYP3A4 involved |
| Half-life | Variable: 6 to 9 days with normal BMI 16 days if BMI >30 |
| Excretion | Fecal (86%) and renal (3%) |
| Identifiers | |
| CAS number | 158681-13-1  |
| ATC code | A08AX01 |
| PubChem | CID 104850 |
| IUPHAR ligand | 743 |
| DrugBank | DB06155 |
| ChemSpider | 94641 |
| UNII | RML78EN3XE |
| KEGG | D05731 |
| ChEMBL | CHEMBL111 |
| Chemical data | |
| Formula | C22H21Cl3N4O |
| Mol. mass | 463.79 g/mol |
| SMILES | eMolecules & PubChem |
|
|
 (what is this?) (verify) |
Rimonabant (also known as SR141716; trade names Acomplia, Bethin, Monaslim, Remonabent, Riobant, Slimona, Rimoslim, Zimulti,[3] and Riomont) is an anorectic antiobesity drug that has been withdrawn from the market. It is an inverse agonist for the cannabinoid receptor CB1.[4] 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later released a press statement stating the drug had been suspended.[5][6] Approval of the drug was officially withdrawn by the EMEA on 16 January 2009.[7]
Contents |
[edit] 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.[citation needed] 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.[2] 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[8] 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.[9]
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.[1]
[edit] 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.[10] 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[11] 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.
[edit] Other uses
[edit] 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 11/2-fold".[12]
[edit] 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.[13]
[edit] 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.[14]
[edit] Blockage of cannabis effects
Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9-tetrahydrocannabinol (THC) in humans without affecting the pharmacokinetics.[15]
[edit] Effect on physical activity
Rimonabant reduces voluntary wheel running in laboratory mice.[16]
[edit] Effect on male fertility
Rimonabant significantly increased human sperm motility and viability in vitro.[17]
[edit] Reaction
Rimonabant can be synthesized as follows:[18]
[edit] References
- ^ a b "Anti-obesity drug use suspended". BBC News. 23 October 2008. http://news.bbc.co.uk/2/hi/health/7687311.stm. Retrieved 4 March 2010.
- ^ a b "Zimulti Acomplia Report - Diet Drug Acomplia / Zimulti Gets Thumbs Down From FDA Panel". Acompliareport.com. 2007-06-13. http://www.acompliareport.com/News/news-061807.htm. Retrieved 2010-03-19.
- ^ Rimonabant was sold in the United Kingdom by Sanofi-Aventis and in Denmark by Sanofi-Synthelabo under the trade name Acomplia, the name used in 18 countries, as of 2007. Bethin, Monaslim, Remonabent, Riobant, Slimona and Rimoslim are generic forms available in India. If approved in the United States, it is intended to be marketed under the name Zimulti.
- ^ Fong TM, Heymsfield SB (September 2009). "Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions". Int J Obes (Lond) 33 (9): 947–55. doi:10.1038/ijo.2009.132. PMID 19597516.
- ^ "European Medicines Agency". Emea.europa.eu. 2010-02-15. http://www.emea.europa.eu/. Retrieved 2010-03-19.
- ^ "Sanofi-aventis - A diversified healthcare company, focused on patients’ needs". En.sanofi-aventis.com. http://en.sanofi-aventis.com/. Retrieved 2010-03-19.
- ^ "Microsoft Word - Zimulti _Rimonabant_ Public Statement" (PDF). http://www.emea.europa.eu/humandocs/PDFs/EPAR/zimulti/3956009en.pdf. Retrieved 2010-03-19.
- ^ Auteur: Femke Gebruers. "Article from the Belgian newspaper De Standaard". Standaard.be. http://www.standaard.be/Artikel/Detail.aspx?artikelId=GN2UC1SD. Retrieved 2010-03-19.
- ^ "Article from the Swedish TV station TV 4 website". Tv4.se. 2008-03-06. http://www.tv4.se/nyheter/472499.html. Retrieved 2010-03-19.[dead link]
- ^ "Kassen müssen nicht für "Acomplia" zahlen". tagesschau.de. 2006-10-17. http://www.tagesschau.de/aktuell/meldungen/0,,OID6010180,00.html. Retrieved 2007-06-13.
- ^ "Suicide risk fears over diet pill". BBC News. 15 June 2007. http://news.bbc.co.uk/2/hi/health/6755665.stm. Retrieved 4 March 2010.
- ^ Cahill K, Ussher M (2007). Cahill, Kate. ed. "Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation". Cochrane database of systematic reviews (Online) (4): CD005353. doi:10.1002/14651858.CD005353.pub3. PMID 17943852.
- ^ Maldonado R, Valverde O, Berrendero F (2006). "Involvement of the endocannabinoid system in drug addiction". Trends Neurosci. 29 (4): 225–32. doi:10.1016/j.tins.2006.01.008. PMID 16483675.
- ^ Deadwyler SA, Goonawardena AV, Hampson RE (2007). "Short-term memory is modulated by the spontaneous release of endocannabinoids: evidence from hippocampal population codes". Behavioural pharmacology 18 (5–6): 571–80. doi:10.1097/FBP.0b013e3282ee2adb. PMID 17762525.
- ^ Huestis MA, Gorelick DA, Heishman SJ, et al. (2001). "Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716". Arch. Gen. Psychiatry 58 (4): 322–8. doi:10.1001/archpsyc.58.4.322. PMID 11296091.
- ^ Keeney BK, Raichlen DA, Meek TH, Wijeratne RS, Middleton KM, Gerdeman GL, Garland T, Jr. (2008). "Differential response to a selective cannabinoid receptor antagonist (SR141716: rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behavior". Behavioural Pharmacology 19 (8): 812–820. doi:10.1097/FBP.0b013e32831c3b6b. PMID 19020416.
- ^ Aguila S, Guido C, Santoro A, Gazzerro P, Laezza C, Baffa MF, Ando S, Bifulco M (2010). "Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm". Br J Pharmacol 159 (4): 831–41. PMID 20067470.
- ^ Yoshioka, T.; Fujita, T.; Kanai, T.; Aizawa, Y.; Kurumada, T.; Hasegawa, K.; Horikoshi, H. (1989). "Studies on hindered phenols and analogs. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation". Journal of Medicinal Chemistry 32 (2): 421. doi:10.1021/jm00122a022. PMID 2913302.
|
