Bioorganic & Medicinal Chemistry 2008-07-01

2-phenyl-4-piperazinylbenzimidazoles: orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor.

Jeffrey C Pelletier, Murty Chengalvala, Josh Cottom, Irene Feingold, Lloyd Garrick, Daniel Green, Diane Hauze, Christine Huselton, James Jetter, Wenling Kao, Gregory S Kopf, Joseph T Lundquist, Charles Mann, John Mehlmann, John Rogers, Linda Shanno, Jay Wrobel

Index: Bioorg. Med. Chem. 16(13) , 6617-40, (2008)

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Abstract

Antagonism of the gonadotropin releasing hormone (GnRH) receptor has shown positive clinical results in numerous reproductive tissue disorders such as endometriosis, prostate cancer and others. Traditional therapy has been limited to peptide agonists and antagonists. Recently, small molecule GnRH antagonists have emerged as potentially new treatments. This article describes the discovery of 2-phenyl-4-piperazinylbenzimidazoles as small molecule GnRH antagonists with nanomolar potency in in vitro binding and functional assays, excellent bioavailability (rat %F>70) and demonstrated oral activity in a rat model having shown significant serum leuteinizing hormone (LH) suppression.