Biarylcarbamoylindolines are novel and selective 5-HT2C receptor inverse agonists: Identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent

The evolution, synthesis, and biological activity of a novel series of 5-HT 2C receptor inverse agonists are reported. Biarylcarbamoylindolines have be en identified with excellent 5-HT2C affinity and selectivity over 5-HT2A re ceptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been disco vered with additional selectivity over the closely related 5-HT2B receptor. Compounds from this series are inverse agonists at the human cloned 5-HT2C receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med . Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in a nimal models of anxiety. On the basis of their favorable biological profile , 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluati on to determine their therapeutic potential for the treatment of CNS disord ers such as depression and anxiety.