Cannabinoids constitute an area of intensive research, both in industry and in academic institutions. Approximately 15 years ago, tremendous progress has been made in the molecular characterization of endogenous cannabinoids and their receptors. Cannabinoid CB1 receptor antagonists showed clinical efficacy in the treatment of obesity and improved cardiovascular and metabolic risk factors. They have good prospects in other therapeutic areas, including smoking and alcohol addiction. Solvay's research achievements in the fast-moving field of CB1 receptor antagonists are highlighted in relation with the general state of the art. Solvay pursued several medicinal chemistry strategies. The application of the concept of conformational constraint led to the discovery of rigidified analogs of the prototypic CB1 receptor antagonist rimonabant. Modifications at the 4-position of the pyrazole ring in rimonabant led to a novel compound with retained CB1 receptor antagonistic potency but with a different predicted biodegradation profile. Bioisosteric replacement of the central heterocyclic pyrazole ring in rimonabant yielded imidazoles, triazoles and thiazoles as selective CB1 receptor antagonists. Dedicated medium throughput screening efforts delivered one diarylpyrazoline hit. This initial hit showed poor pharmacokinetic properties but could be successfully optimized into the orally active and highly CB1/CB2 receptor selective drug candidate ibipinabant, which is the subject of a development agreement between Solvay and Bristol-Myers Squibb.
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