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Discovery of 6-({4-[2-(4- tert -Butylphenyl)-1 H -benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): An Orally Active Antagonist of the Gonadotropin Releasing Hormone Receptor (GnRH-R)

2009; American Chemical Society; Volume: 52; Issue: 7 Linguagem: Inglês

10.1021/jm801572m

1520-4804

Jeffrey C. Pelletier, Murty Chengalvala, Joshua E. Cottom, Irene Feingold, Daniel M. Green, Diane B. Hauze, Christine 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, C O Tio, Jay Wrobel,

DNA and Nucleic Acid Chemistry

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.