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)

  • J Med Chem. 2009 Apr 9;52(7):2148-52. doi: 10.1021/jm801572m.
Jeffrey C Pelletier  1 ,  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
Affiliations
  • 1. Department of Chemical Sciences, Musculoskeletal Biology, and Drug Safety and Metabolism, Wyeth Research, Collegeville, Pennsylvania 19426, USA.
PMID: 19271735 DOI: 10.1021/jm801572m
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.

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