TM38837

Target: CB1
Status: Phase I

In 2009, 7TM Pharma successfully conducted and completed a Phase I clinical trial with TM38837, which was discovered internally at 7TM Pharma and is being developed for treatment of obesity and related metabolic disorders. The Phase I clinical trial was a first in man single ascending dose study in healthy male subjects with additional cohorts in other populations. The aim of the study was to determine the safety and tolerability of a range of single ascending doses of TM38837 and additionally to describe the pharmacokinetic properties of the compound.

TM38837 is a first in class, second generation CB1 receptor antagonist. It was designed to circumvent the CNS side effect profile displayed by the first generation CB1 receptor antagonists, through its restriction to peripherally located CB1 receptors in the body. This approach is in contrast to the first generation CB1 receptor antagonists which focused on targeting also CB1 receptors within the CNS, which although clinically effective, had unfavorable CNS mediated side effect profiles including depression and anxiety.

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. The compound 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.

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.