TM38837

Target: CB1
Status: Pre-clinical development

7TM Pharma has selected a pre-clinical development candidate, TM38837, for the treatment of obesity and related metabolic diseases. TM38837 derives from 7TM Pharma’s discovery program targeting the development of Cannabinoid type 1 receptor antagonists (CB1 antagonists) acting specifically in the periphery of the body.

TM38837 has shown a substantial and robust weight reduction effect in various chronic animal models for obesity. Importantly, it has further been shown to have a very favorable side effect profile in various animal models compared to other known CB1 antagonists.

CB1 antagonists have been demonstrated in a number of clinical trials to reduce body weight and improve obesity associated risk factors, for example Type 2 diabetes. Compounds currently in clinical development and on the market exert their effects via CB1 receptors both in the periphery and in the brain. However, the presence of these compounds in the brain is believed to lead to undesired side effects such as depression and anxiety reported for these compounds. TM38837 has been designed to exclusively exert its therapeutic effect through CB1 receptors located in the peripheral tissue, thereby avoiding these undesired side effects.

The CB1 antagonist program became a part of 7TM Pharma’s project portfolio through the acquisition of the French Biotech company, CareX SA in May 2006. The program utilizes a novel approach to the development of CB1 antagonists for the treatment of obesity, aiming at a CB1 antagonist primarily acting on the peripheral receptor with reduced central nervous system activity that may cause CNS-related side effects.

Cannabinoid receptors are found in several areas of the nervous system and peripheral tissues. In the brain, activation of CB1, a 7TM receptor, appears to provoke food intake even in the setting of satiety. In fat cells, activation of CB1 promotes lipogenesis and inhibits production of the beneficial hormone adiponectin. Other peripheral organs and tissues, in particular the liver, pancreas and skeletal muscles, might also be involved in the control of energy balance by endocannabinoids, e.g. stimulation of CB1 in the liver increases de novo fatty acid biosynthesis. Thus CB1 and the associated endogenous ligands, the endocannabinoids, play an important role in the regulation of appetite behavior and overall energy metabolism. Through inhibition of food consumption and effects on peripheral metabolic parameters, CB1 antagonists offer a promising new class of anti-obesity treatments.

(1) V Di Marzo et al (2005), Nature Neuroscience, 8(5), 585-589
(2) U Pagotto et al (2006), J Endocrinol. Invest., 29 (suppl. to no.3), 66-76