Isoindolone derivatives, a new class of 5-HT2C antagonists: synthesis and biological evaluation.

Abstract Two independent approaches resulted in the identification of a series of isoindolone derivatives as potent and selective 5-HT 2C antagonists. From a Medicinal Chemistry perspective this template was considered interesting as it allowed the incorporation of the carbon–carbon double bond of an earlier dihydropyrrolone series in an aromatic system within a comparatively simple and compact motif. Additionally an in silico screening approach of the corporate database using a 5-HT 2C pharmacophore model resulted in the identification of a related structure containing this template. The strategy used to optimise potency at the target receptor and to improve the pharmacokinetic profile is described, resulting in molecules combining high potency with good selectivity and oral bioavailability.