Simultaneous biological optimization and structural simplification of a pendant heterocyclic thiobenzimidazolone on a series of 2-phenyl-4-(piperazin-1-yl)benzimidazole antagonists of the Gonadotropin Releasing Hormone Receptor

MEDI 80

Jeffrey C. Pelletier1, Murty V. Chengalvala2, Joshua E. Cottom2, Lloyd Garrick1, James Jetter3, Wenling Kao3, Linda Shanno2, and Jay Wrobel, wrobelj@wyeth.com4. (1) Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, (2) Department of Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, (3) Department of Chemical & Screening Sciences, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, (4) Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426
We recently described the preparation of a series of 2-phenyl-4-(piperazin-1-yl)benzimidazoles as small molecule, orally available antagonists of the Gonadotropin Releasing Hormone Receptor. Excellent biological activity requires that the (1-piperazinyl)-4-benzimidazole template have pendant cyclic functionality connected via a methylene or an ethoxy linker. The lead series contains a thiobenzimidazolone as the pendant heterocycle (R = thiobenzimidazolone). Our efforts were directed at simplifying the pendant heterocyclic structure to remove the thiocarbonyl and optimize biological activity. Most compounds were prepared using parallel synthesis techniques. Chemistry, receptor binding and functional, cell-based biology in human and rat species will be discussed.

 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007