Jump to content

Rimonabant: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
(32 intermediate revisions by 19 users not shown)
Line 1: Line 1:
{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Watchedfields = changed
| Watchedfields = changed
Line 53: Line 54:
}}
}}


'''Rimonabant''' (also known as '''SR141716'''; trade names '''Acomplia''', '''Zimulti''')<ref>{{cite web|title=Rimonabant|url=http://adisinsight.springer.com/drugs/800007737|publisher=AdisInsight|access-date=21 February 2017|language=en}}</ref> is an [[anorectic]] [[anti-obesity|antiobesity drug]] that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States.<ref name=Sam2011rev>{{cite journal|last1=Sam|first1=AH|last2=Salem|first2=V|last3=Ghatei|first3=MA|title=Rimonabant: From RIO to Ban.|journal=Journal of Obesity|date=2011|volume=2011|pages=432607|pmid=21773005|pmc=3136184|doi=10.1155/2011/432607}}</ref><ref name=Moreira2009>{{cite journal|last1=Moreira|first1=FA|last2=Crippa|first2=JA|title=The psychiatric side-effects of rimonabant.|journal=Revista Brasileira de Psiquiatria |date=June 2009|volume=31|issue=2|pages=145–53|pmid=19578688|doi=10.1590/s1516-44462009000200012|doi-access=free}}</ref> Rimonabant is an [[inverse agonist]] for the [[cannabinoid receptor CB1 | cannabinoid receptor CB<sub>1</sub>]] and was the first drug approved in that class.<ref name="pmid19597516">{{cite journal |vauthors=Fong TM, Heymsfield SB |title= Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions |journal= International Journal of Obesity|volume= 33 |issue= 9 |pages= 947–55 |date=September 2009 |pmid= 19597516 |doi= 10.1038/ijo.2009.132 |doi-access= free }}</ref><ref name=IHS>{{cite news|title=European Approval Comes Early for Sanofi-Aventis' Acomplia|url=https://www.ihs.com/country-industry-forecasting.html?ID=106599233|work=IHS|date=June 23, 2006}}</ref>
'''Rimonabant''' (also known as '''SR141716'''; trade names '''Acomplia''', '''Zimulti''')<ref>{{cite web|title=Rimonabant|url=http://adisinsight.springer.com/drugs/800007737|publisher=AdisInsight|access-date=21 February 2017|language=en}}</ref> is an [[anorectic]] [[anti-obesity|antiobesity drug]] approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States.<ref name=Sam2011rev>{{cite journal | vauthors = Sam AH, Salem V, Ghatei MA | title = Rimonabant: From RIO to Ban | journal = Journal of Obesity | volume = 2011 | pages = 432607 | date = 2011 | pmid = 21773005 | pmc = 3136184 | doi = 10.1155/2011/432607 | doi-access = free }}</ref><ref name=Moreira2009>{{cite journal | vauthors = Moreira FA, Crippa JA | title = The psychiatric side-effects of rimonabant | journal = Revista Brasileira de Psiquiatria | volume = 31 | issue = 2 | pages = 145–153 | date = June 2009 | pmid = 19578688 | doi = 10.1590/s1516-44462009000200012 | doi-access = free }}</ref> Rimonabant is an [[inverse agonist]] for the [[cannabinoid receptor CB1 | cannabinoid receptor CB<sub>1</sub>]] and was first-in-class for clinical development.<ref name="pmid19597516">{{cite journal | vauthors = Fong TM, Heymsfield SB | title = Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions | journal = International Journal of Obesity | volume = 33 | issue = 9 | pages = 947–955 | date = September 2009 | pmid = 19597516 | doi = 10.1038/ijo.2009.132 | doi-access = free }}</ref><ref name=IHS>{{cite news|title=European Approval Comes Early for Sanofi-Aventis' Acomplia|url=https://www.ihs.com/country-industry-forecasting.html?ID=106599233|work=IHS|date=June 23, 2006}}</ref>


==History==
==History==
{{See also|Discovery and development of Cannabinoid Receptor 1 Antagonists}}
{{See also|Discovery and development of Cannabinoid Receptor 1 Antagonists}}
Rimonabant is a selective CB<sub>1</sub> [[receptor (biochemistry)|receptor]] blocker and was [[drug discovery|discovered]] and [[drug development|developed]] by [[Sanofi|Sanofi-Aventis]];<ref name=Barth_1999>{{Citation | last1 = Barth | first1 = F. | last2 =Rinaldi-Carmona | first2 = M. | title = The Development of Cannabinoid Antagonists| journal =Current Medicinal Chemistry| volume = 6 | pages = 745–755| year = 1999 | url=http://www.bentham.org/cmc/contabs/vol6-8.html | pmid = 10469889 | issue = 8 }}</ref>
Rimonabant is a selective CB<sub>1</sub> [[receptor (biochemistry)|receptor]] blocker and was [[drug discovery|discovered]] and [[drug development|developed]] by [[Sanofi|Sanofi-Aventis]].<ref name=Barth_1999>{{cite journal | vauthors = Barth F, Rinaldi-Carmona M | title = The development of cannabinoid antagonists | journal = Current Medicinal Chemistry | volume = 6 | issue = 8 | pages = 745–755 | date = August 1999 | pmid = 10469889 | doi = 10.2174/0929867306666220401143808 | s2cid = 247893317 }}</ref>


On 21 June 2006, the [[European Commission]] approved the sale of rimonabant in the then-25-member European Union as a prescription drug for use in conjunction with diet and exercise for patients with a [[body mass index|body mass index (BMI)]] greater than 30&nbsp;kg/m<sup>2</sup>, or patients with a BMI greater than 27&nbsp;kg/m<sup>2</sup> with associated risk factors, such as type 2 [[diabetes]] or [[dyslipidaemia]].<ref name=EMAlabel>{{cite web|title=Acomplia EPAR|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000666/WC500021282.pdf|publisher=EMA|date=January 30, 2009}} From [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000666/human_med_000623.jsp EMA index page]</ref> It was first in its class to be approved anywhere in the world.<ref name=IHS/>
On 21 June 2006, the [[European Commission]] approved the sale of rimonabant in the then-25-member European Union as a prescription drug for use in conjunction with diet and exercise for patients with a [[body mass index|body mass index (BMI)]] greater than 30&nbsp;kg/m<sup>2</sup>, or patients with a BMI greater than 27&nbsp;kg/m<sup>2</sup> with associated risk factors, such as type 2 [[diabetes]] or [[dyslipidaemia]].<ref name=EMAlabel>{{cite web|title=Acomplia EPAR|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000666/WC500021282.pdf|publisher=EMA|date=January 30, 2009|access-date=February 21, 2017|archive-date=February 22, 2017|archive-url=https://web.archive.org/web/20170222105745/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000666/WC500021282.pdf|url-status=dead}} From [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000666/human_med_000623.jsp EMA index page] {{Webarchive|url=https://web.archive.org/web/20170222105742/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F000666%2Fhuman_med_000623.jsp |date=2017-02-22 }}</ref> It was first in its class to be approved anywhere in the world.<ref name=IHS/>


Rimonabant was submitted to the [[Food and Drug Administration]] (FDA) for approval in the United States in 2005; in 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval<ref>{{cite news|last1=Saul|first1=Stephanie|title=F.D.A. Panel Rejects Drug for Obesity|url=https://query.nytimes.com/gst/fullpage.html?res=9C0CE7D9143FF937A25755C0A9619C8B63|work=The New York Times|date=14 June 2007}}</ref> and two weeks later the company withdrew the application.<ref>{{cite news|title=Sanofi-Aventis Drops Application for Drug|url=https://www.nytimes.com/2007/06/30/business/30drug.html|work=The New York Times|date=30 June 2007}}</ref>
Rimonabant was submitted to the [[Food and Drug Administration]] (FDA) for approval in the United States in 2005; in 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval.<ref>{{cite news| vauthors = Saul S |title=F.D.A. Panel Rejects Drug for Obesity|url=https://query.nytimes.com/gst/fullpage.html?res=9C0CE7D9143FF937A25755C0A9619C8B63|work=The New York Times|date=14 June 2007}}</ref> The application was deemed ''not-approvable'' by FDA, and the company cancelled plans for a re-submission.<ref>{{cite news|title=Sanofi-Aventis Drops Application for Drug|url=https://www.nytimes.com/2007/06/30/business/30drug.html|work=The New York Times|date=30 June 2007}}</ref>


The drug was approved in Brazil in April 2007.<ref name=Moreira2009/>
The drug was approved in Brazil in April 2007.<ref name=Moreira2009/>


In October 2008, the [[European Medicines Agency]] recommended the suspension of Acomplia after the [[Committee for Medicinal Products for Human Use]] (CHMP) had determined that the risks of Acomplia [[risk-benefit analysis|outweighed its benefits]] due to the risk of serious psychiatric problems, including suicide.<ref>{{cite web |url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2009/11/news_detail_000244.jsp|title=The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia|publisher=European Medicines Agency|date=23 October 2008|access-date=18 January 2016}}</ref> In November 2008 an advisory committee in Brazil recommended suspension as well, and that month Sanofi-Aventis suspended sale of the drug worldwide.<ref name=Moreira2009/> The EMA approval was withdrawn in January 2009.<ref name="euwith">{{cite news|url=http://news.bbc.co.uk/2/hi/health/7687311.stm|title=Anti-obesity drug use suspended|date=23 October 2008|work=BBC News|access-date=4 March 2010}}</ref><ref>{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500012189.pdf |title=Public Statement on Acomplia (rimonabant) Withdrawal of the Marketing Authorisation in the European Union|publisher=European Medicines Agency |date=30 January 2009 |access-date=18 January 2016}}</ref> In 2009 India prohibited the manufacture and sale of the drug.<ref name=ban>{{cite web|url=http://www.cdsco.nic.in/writereaddata/DBC.pdfl|title=Drugs banned in India|publisher=Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India|access-date=2013-09-17}}</ref>
In October 2008, the [[European Medicines Agency]] recommended the suspension of Acomplia after the [[Committee for Medicinal Products for Human Use]] (CHMP) had determined that the risks of Acomplia [[risk-benefit analysis|outweighed its benefits]] due to the risk of serious psychiatric problems, including suicide.<ref>{{cite web |url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2009/11/news_detail_000244.jsp|title=The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia|publisher=European Medicines Agency|date=23 October 2008|access-date=18 January 2016}}</ref> In November 2008 an advisory committee in Brazil recommended suspension as well, and that month Sanofi-Aventis suspended sale of the drug worldwide.<ref name=Moreira2009/> The EMA approval was withdrawn in January 2009.<ref name="euwith">{{cite news|url=http://news.bbc.co.uk/2/hi/health/7687311.stm|title=Anti-obesity drug use suspended|date=23 October 2008|work=BBC News|access-date=4 March 2010}}</ref><ref>{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500012189.pdf |title=Public Statement on Acomplia (rimonabant) Withdrawal of the Marketing Authorisation in the European Union|publisher=European Medicines Agency |date=30 January 2009 |access-date=18 January 2016}}</ref> In 2009 India prohibited the manufacture and sale of the drug.<ref name=ban>{{cite web|url=http://www.cdsco.nic.in/writereaddata/DBC.pdfl|title=Drugs banned in India|publisher=Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India|access-date=2013-09-17|archive-date=2017-02-22|archive-url=https://web.archive.org/web/20170222111445/http://www.cdsco.nic.in/writereaddata/DBC.pdfl|url-status=dead}}</ref>


==Adverse effects==
==Adverse effects==
Data from clinical trials submitted to regulatory authorities showed that rimonabant caused depressive disorders or mood alterations in up to 10% of subjects and suicidal ideation in around 1%, and in Europe it was contraindicated for people with any psychiatric disorder, including depressed or suicidal individuals.<ref name=EMAlabel/>
Data from clinical trials submitted to regulatory authorities showed that rimonabant caused depressive disorders or mood alterations in up to 10% of subjects and suicidal ideation in around 1%, and in Europe it was contraindicated for people with any psychiatric disorder, including depressed or suicidal individuals.<ref name=EMAlabel/> Data from a large, randomized, clinical trial (CRESCENDO) with > 9000 patients receiving rimonabant treatment demonstrated a rate of psychiatric adverse events (anxiety, depression, depressed mood, or insomnia) of greater than 30%.<ref>{{cite journal | vauthors = Topol EJ, Bousser MG, Fox KA, Creager MA, Despres JP, Easton JD, Hamm CW, Montalescot G, Steg PG, Pearson TA, Cohen E, Gaudin C, Job B, Murphy JH, Bhatt DL | display-authors = 6 | title = Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial | journal = Lancet | volume = 376 | issue = 9740 | pages = 517–523 | date = August 2010 | pmid = 20709233 | doi = 10.1016/S0140-6736(10)60935-X | s2cid = 36404292 }}</ref>


Additionally, nausea and upper respiratory tract infections were very common adverse effects (occurring in more than 10% of people); common adverse effects (occurring in between 1% and 10% of people) included [[gastroenteritis]], anxiety, irritability, insomnia and other sleep disorders, hot flushes, diarrhea, vomiting, dry or itchy skin, tendonitis, muscle cramps and spasms, fatigue, flu-like symptoms, and increased risk of falling.
Additionally, nausea and upper respiratory tract infections were very common adverse effects (occurring in more than 10% of people); common adverse effects (occurring in between 1% and 10% of people) included [[gastroenteritis]], anxiety, irritability, insomnia and other sleep disorders, hot flushes, diarrhea, vomiting, dry or itchy skin, tendonitis, muscle cramps and spasms, fatigue, flu-like symptoms, and increased risk of falling.


The FDA's advisory committee raised concerns that based on animal data, it appeared that the [[therapeutic window]] with regard to CNS toxicity, and specifically seizures was almost nonexistent; the therapeutic dose and the dose that caused seizures in animals appeared to be the same.<ref name=Moreira2009/><ref>{{cite web|title=FDA Briefing Document NDA 21-888 Zimulti (rimonabant) Tablets, 20|url=https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4306b1-fda-backgrounder.pdf|publisher=FDA|date=June 13, 2007}}</ref><ref>{{cite web|last1=Davis-Bruno|first1=Karen|title=Nonclinical Overview: CNS Toxicity with Rimonabant|url=https://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4306s1-09-FDA-Bruno.ppt|publisher=FDA, Division of Metabolism & Endocrinology Products|date=June 13, 2007}}</ref>
The FDA's advisory committee concurred with concerns raised by the review divisions. Based on human and on animal data, it appeared that the [[therapeutic window]] with regard to CNS toxicity, and specifically seizures was narrow.<ref name=Moreira2009/><ref>{{cite web|title=FDA Briefing Document NDA 21-888 Zimulti (rimonabant) Tablets, 20|url=https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4306b1-fda-backgrounder.pdf|publisher=FDA|date=June 13, 2007}}</ref><ref>{{cite web| vauthors = Davis-Bruno K |title=Nonclinical Overview: CNS Toxicity with Rimonabant|url=https://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4306s1-09-FDA-Bruno.ppt|publisher=FDA, Division of Metabolism & Endocrinology Products|date=June 13, 2007}}</ref>


When the EMA reviewed [[postmarketing surveillance]] data, it found that the risk of psychiatric disorders in people taking rimonabant was doubled.<ref name=Moreira2009/>
EMA [[postmarketing surveillance]] data suggested that the risk of psychiatric disorders in people taking rimonabant was doubled.<ref name=Moreira2009/>

==Pharmacology==

===Pharmacodynamics===
Rimonabant is an [[inverse agonist]] of the [[cannabinoid receptor|cannabinoid]] [[CB1 receptor|CB<sub>1</sub> receptor]]. Originally thought to be [[binding selectivity|selective]] for the CB<sub>1</sub> receptor, rimonabant was subsequently also found to act as an [[receptor antagonist|antagonist]] of the [[μ-opioid receptor]].<ref name="pmid22771770">{{cite journal | vauthors = Seely KA, Brents LK, Franks LN, Rajasekaran M, Zimmerman SM, Fantegrossi WE, Prather PL | title = AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies | journal = Neuropharmacology | volume = 63 | issue = 5 | pages = 905–915 | date = October 2012 | pmid = 22771770 | pmc = 3408547 | doi = 10.1016/j.neuropharm.2012.06.046 }}</ref>


==Chemistry==
==Chemistry==
The chemical synthesis of rimonabant is described as follows:<ref>{{Cite journal |doi= 10.1021/jm00122a022 |title= Studies on hindered phenols and analogs. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation |year= 1989 |author= Yoshioka, T.|journal= Journal of Medicinal Chemistry |volume= 32 |pages= 421–8 |pmid= 2913302 |issue= 2 |display-authors=etal}}</ref>{{Failed verification|date=June 2019}}
The chemical synthesis of rimonabant is described as follows:<ref>{{cite journal | vauthors = Yoshioka T, Fujita T, Kanai T, Aizawa Y, Kurumada T, Hasegawa K, Horikoshi H | title = Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation | journal = Journal of Medicinal Chemistry | volume = 32 | issue = 2 | pages = 421–428 | date = February 1989 | pmid = 2913302 | doi = 10.1021/jm00122a022 }}</ref>{{Failed verification|date=June 2019}}


[[File:Rimonabant.png|600px]]
[[File:Rimonabant.png|600px]]


== Research ==
== Research ==
Along with the clinical trials in obesity that generated the data submitted to regulatory authorities,<ref>{{cite journal | vauthors = Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J | date = Feb 2006 | title = Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial | journal = JAMA | volume = 295 | issue = 7| pages = 761–75 | doi = 10.1001/jama.295.7.761 | pmid = 16478899 | doi-access = free }}</ref> rimonabant was also studied in clinical trials as a potential treatment for other conditions,<ref name=Moreira2009/> including diabetes, atherosclerosis, and smoking cessation.<ref>{{cite journal|last1=Cahill|first1=K|last2=Ussher|first2=MH|title=Cannabinoid type 1 receptor antagonists for smoking cessation.|journal=The Cochrane Database of Systematic Reviews|date=16 March 2011|issue=3|pages=CD005353|pmid=21412887|doi=10.1002/14651858.CD005353.pub4|pmc=6486173}}</ref><ref name="pmid16483675">{{cite journal |vauthors=Maldonado R, Valverde O, Berrendero F |title=Involvement of the endocannabinoid system in drug addiction |journal= Trends in Neurosciences|volume=29 |issue=4 |pages=225–32 |year=2006 |pmid=16483675 |doi=10.1016/j.tins.2006.01.008 |s2cid=16125335 }}</ref>
Along with the clinical trials in obesity that generated the data submitted to regulatory authorities,<ref>{{cite journal | vauthors = Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J | title = Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial | journal = JAMA | volume = 295 | issue = 7 | pages = 761–775 | date = February 2006 | pmid = 16478899 | doi = 10.1001/jama.295.7.761 | doi-access = free }}</ref> rimonabant was also studied in clinical trials<ref name=Moreira2009/> for diabetes, atherosclerosis, and smoking cessation.<ref>{{cite journal | vauthors = Cahill K, Ussher MH | title = Cannabinoid type 1 receptor antagonists for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 2011 | issue = 3 | pages = CD005353 | date = March 2011 | pmid = 21412887 | pmc = 6486173 | doi = 10.1002/14651858.CD005353.pub4 }}</ref><ref name="pmid16483675">{{cite journal | vauthors = Maldonado R, Valverde O, Berrendero F | title = Involvement of the endocannabinoid system in drug addiction | journal = Trends in Neurosciences | volume = 29 | issue = 4 | pages = 225–232 | date = April 2006 | pmid = 16483675 | doi = 10.1016/j.tins.2006.01.008 | s2cid = 16125335 }}</ref>

== See also ==
*[[Drinabant]]{{snd}}a cannabinoid receptor antagonist developed for prescription drug use that triggered severe psychiatric side effects.


==References==
== References ==
{{Reflist|30em}}
{{Reflist}}


{{Antiobesity preparations}}
{{Antiobesity preparations}}
{{Cannabinoids}}
{{Cannabinoids}}
{{Cannabinoid receptor modulators}}
{{Cannabinoidergics}}
{{Opioid receptor modulators}}
{{Opioidergics}}


[[Category:Hydrazides]]
[[Category:Hydrazides]]
Line 96: Line 105:
[[Category:Anxiogenics]]
[[Category:Anxiogenics]]
[[Category:CB1 receptor antagonists]]
[[Category:CB1 receptor antagonists]]
[[Category:Chloroarenes]]
[[Category:4-Chlorophenyl compounds]]
[[Category:Piperidines]]
[[Category:1-Piperidinyl compounds]]
[[Category:Pyrazoles]]
[[Category:Pyrazoles]]
[[Category:Withdrawn drugs]]
[[Category:Withdrawn drugs]]
[[Category:Cannabinoids]]
[[Category:Cannabinoids]]
[[Category:Mu-opioid receptor antagonists]]
[[Category:Pyrazolecarboxamides]]
[[Category:Pyrazolecarboxamides]]
[[Category:Opioid antagonists]]
[[Category:Withdrawn anti-obesity drugs]]

Revision as of 17:49, 7 September 2024

Rimonabant
Clinical data
AHFS/Drugs.comConsumer Drug Information
License data
Pregnancy
category
  • Not assigned, use not recommended
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • Withdrawn from European and Brazilian markets; not approved elsewhere[1][2]
Pharmacokinetic data
BioavailabilityUndetermined
Protein bindingNearly 100%
MetabolismHepatic, CYP3A4 involved
Elimination half-lifeVariable:
6 to 9 days with normal BMI
16 days if BMI >30
ExcretionFecal (86%) and renal (3%)
Identifiers
  • 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.210.978 Edit this at Wikidata
Chemical and physical data
FormulaC22H21Cl3N4O
Molar mass463.79 g·mol−1
3D model (JSmol)
  • O=C(NN1CCCCC1)c4nn(c2ccc(Cl)cc2Cl)c(c3ccc(Cl)cc3)c4C
  • InChI=1S/C22H21Cl3N4O/c1-14-20(22(30)27-28-11-3-2-4-12-28)26-29(19-10-9-17(24)13-18(19)25)21(14)15-5-7-16(23)8-6-15/h5-10,13H,2-4,11-12H2,1H3,(H,27,30) checkY
  • Key:JZCPYUJPEARBJL-UHFFFAOYSA-N checkY
  (verify)

Rimonabant (also known as SR141716; trade names Acomplia, Zimulti)[3] is an anorectic antiobesity drug approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States.[1][2] Rimonabant is an inverse agonist for the cannabinoid receptor CB1 and was first-in-class for clinical development.[4][5]

History

See also: Discovery and development of Cannabinoid Receptor 1 Antagonists

Rimonabant is a selective CB1 receptor blocker and was discovered and developed by Sanofi-Aventis.[6]

On 21 June 2006, the European Commission approved the sale of rimonabant in the then-25-member European Union as a prescription drug for use in conjunction with diet and exercise for patients with a body mass index (BMI) 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.[7] It was first in its class to be approved anywhere in the world.[5]

Rimonabant was submitted to the Food and Drug Administration (FDA) for approval in the United States in 2005; in 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval.[8] The application was deemed not-approvable by FDA, and the company cancelled plans for a re-submission.[9]

The drug was approved in Brazil in April 2007.[2]

In October 2008, the European Medicines Agency recommended the suspension of Acomplia after the Committee for Medicinal Products for Human Use (CHMP) had determined that the risks of Acomplia outweighed its benefits due to the risk of serious psychiatric problems, including suicide.[10] In November 2008 an advisory committee in Brazil recommended suspension as well, and that month Sanofi-Aventis suspended sale of the drug worldwide.[2] The EMA approval was withdrawn in January 2009.[11][12] In 2009 India prohibited the manufacture and sale of the drug.[13]

Adverse effects

Data from clinical trials submitted to regulatory authorities showed that rimonabant caused depressive disorders or mood alterations in up to 10% of subjects and suicidal ideation in around 1%, and in Europe it was contraindicated for people with any psychiatric disorder, including depressed or suicidal individuals.[7] Data from a large, randomized, clinical trial (CRESCENDO) with > 9000 patients receiving rimonabant treatment demonstrated a rate of psychiatric adverse events (anxiety, depression, depressed mood, or insomnia) of greater than 30%.[14]

Additionally, nausea and upper respiratory tract infections were very common adverse effects (occurring in more than 10% of people); common adverse effects (occurring in between 1% and 10% of people) included gastroenteritis, anxiety, irritability, insomnia and other sleep disorders, hot flushes, diarrhea, vomiting, dry or itchy skin, tendonitis, muscle cramps and spasms, fatigue, flu-like symptoms, and increased risk of falling.

The FDA's advisory committee concurred with concerns raised by the review divisions. Based on human and on animal data, it appeared that the therapeutic window with regard to CNS toxicity, and specifically seizures was narrow.[2][15][16]

EMA postmarketing surveillance data suggested that the risk of psychiatric disorders in people taking rimonabant was doubled.[2]

Pharmacology

Pharmacodynamics

Rimonabant is an inverse agonist of the cannabinoid CB1 receptor. Originally thought to be selective for the CB1 receptor, rimonabant was subsequently also found to act as an antagonist of the μ-opioid receptor.[17]

Chemistry

The chemical synthesis of rimonabant is described as follows:[18][failed verification]

Research

Along with the clinical trials in obesity that generated the data submitted to regulatory authorities,[19] rimonabant was also studied in clinical trials[2] for diabetes, atherosclerosis, and smoking cessation.[20][21]

See also

  • Drinabant – a cannabinoid receptor antagonist developed for prescription drug use that triggered severe psychiatric side effects.

References

  1. ^ a b Sam AH, Salem V, Ghatei MA (2011). "Rimonabant: From RIO to Ban". Journal of Obesity. 2011: 432607. doi:10.1155/2011/432607. PMC 3136184. PMID 21773005.
  2. ^ a b c d e f g Moreira FA, Crippa JA (June 2009). "The psychiatric side-effects of rimonabant". Revista Brasileira de Psiquiatria. 31 (2): 145–153. doi:10.1590/s1516-44462009000200012. PMID 19578688.
  3. ^ "Rimonabant". AdisInsight. Retrieved 21 February 2017.
  4. ^ Fong TM, Heymsfield SB (September 2009). "Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions". International Journal of Obesity. 33 (9): 947–955. doi:10.1038/ijo.2009.132. PMID 19597516.
  5. ^ a b "European Approval Comes Early for Sanofi-Aventis' Acomplia". IHS. June 23, 2006.
  6. ^ Barth F, Rinaldi-Carmona M (August 1999). "The development of cannabinoid antagonists". Current Medicinal Chemistry. 6 (8): 745–755. doi:10.2174/0929867306666220401143808. PMID 10469889. S2CID 247893317.
  7. ^ a b "Acomplia EPAR" (PDF). EMA. January 30, 2009. Archived from the original (PDF) on February 22, 2017. Retrieved February 21, 2017. From EMA index page Archived 2017-02-22 at the Wayback Machine
  8. ^ Saul S (14 June 2007). "F.D.A. Panel Rejects Drug for Obesity". The New York Times.
  9. ^ "Sanofi-Aventis Drops Application for Drug". The New York Times. 30 June 2007.
  10. ^ "The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia". European Medicines Agency. 23 October 2008. Retrieved 18 January 2016.
  11. ^ "Anti-obesity drug use suspended". BBC News. 23 October 2008. Retrieved 4 March 2010.
  12. ^ "Public Statement on Acomplia (rimonabant) Withdrawal of the Marketing Authorisation in the European Union" (PDF). European Medicines Agency. 30 January 2009. Retrieved 18 January 2016.
  13. ^ "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Archived from the original on 2017-02-22. Retrieved 2013-09-17.
  14. ^ Topol EJ, Bousser MG, Fox KA, Creager MA, Despres JP, Easton JD, et al. (August 2010). "Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial". Lancet. 376 (9740): 517–523. doi:10.1016/S0140-6736(10)60935-X. PMID 20709233. S2CID 36404292.
  15. ^ "FDA Briefing Document NDA 21-888 Zimulti (rimonabant) Tablets, 20" (PDF). FDA. June 13, 2007.
  16. ^ Davis-Bruno K (June 13, 2007). "Nonclinical Overview: CNS Toxicity with Rimonabant". FDA, Division of Metabolism & Endocrinology Products.
  17. ^ Seely KA, Brents LK, Franks LN, Rajasekaran M, Zimmerman SM, Fantegrossi WE, Prather PL (October 2012). "AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies". Neuropharmacology. 63 (5): 905–915. doi:10.1016/j.neuropharm.2012.06.046. PMC 3408547. PMID 22771770.
  18. ^ Yoshioka T, Fujita T, Kanai T, Aizawa Y, Kurumada T, Hasegawa K, Horikoshi H (February 1989). "Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation". Journal of Medicinal Chemistry. 32 (2): 421–428. doi:10.1021/jm00122a022. PMID 2913302.
  19. ^ Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (February 2006). "Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial". JAMA. 295 (7): 761–775. doi:10.1001/jama.295.7.761. PMID 16478899.
  20. ^ Cahill K, Ussher MH (March 2011). "Cannabinoid type 1 receptor antagonists for smoking cessation". The Cochrane Database of Systematic Reviews. 2011 (3): CD005353. doi:10.1002/14651858.CD005353.pub4. PMC 6486173. PMID 21412887.
  21. ^ Maldonado R, Valverde O, Berrendero F (April 2006). "Involvement of the endocannabinoid system in drug addiction". Trends in Neurosciences. 29 (4): 225–232. doi:10.1016/j.tins.2006.01.008. PMID 16483675. S2CID 16125335.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Rimonabant&oldid=1244534155"