Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an

anorectic An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic. The term is (from the Greek ''ἀν-'' (an-) = "without" ...

antiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States. Rimonabant is an

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

for the cannabinoid receptor CB₁ and was the first drug approved in that class.

History

Rimonabant is a selective CB₁ receptor blocker and was discovered and developed by Sanofi-Aventis; 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) Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and hei ...

greater than 30 kg/m², or patients with a BMI greater than 27 kg/m² with associated risk factors, such as type 2

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

dyslipidaemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...

. Fro
EMA index page
/ref> It was first in its class to be approved anywhere in the world. Rimonabant was submitted to the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(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 and two weeks later the company withdrew the application. The drug was approved in Brazil in April 2007. 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. In November 2008 an advisory committee in Brazil recommended suspension as well, and that month Sanofi-Aventis suspended sale of the drug worldwide. The EMA approval was withdrawn in January 2009. In 2009 India prohibited the manufacture and sale of the drug.

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. 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. When the EMA reviewed postmarketing surveillance data, it found that the risk of psychiatric disorders in people taking rimonabant was doubled.

Pharmacology

Pharmacodynamics

Rimonabant is an

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.

Chemistry

The chemical synthesis of rimonabant is described as follows:

Research

Along with the clinical trials in obesity that generated the data submitted to regulatory authorities, rimonabant was also studied in clinical trials as a potential treatment for other conditions, including diabetes, atherosclerosis, and smoking cessation.

References

{{Opioid receptor modulators Hydrazides Anorectics Anxiogenics CB1 receptor antagonists Chlorobenzenes Piperidines Pyrazoles Withdrawn drugs Cannabinoids Mu-opioid receptor antagonists Pyrazolecarboxamides