Journal of medicinal and pharmaceutical chemistry 2009-04-09

Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R).

Jeffrey C Pelletier, Murty V Chengalvala, Joshua E Cottom, Irene B Feingold, Daniel M Green, Diane B Hauze, Christine A Huselton, James W Jetter, Gregory S Kopf, Joseph T Lundquist, Ronald L Magolda, Charles W Mann, John F Mehlmann, John F Rogers, Linda K Shanno, William R Adams, Cesario O Tio, Jay E Wrobel

Index: J. Med. Chem. 52(7) , 2148-52, (2009)

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Abstract

A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.