MEDI 50

B-keto sulfonamides as selective inhibitors of the 11b-HSD1

Manus Ipek, mipek@wyeth.com¹, Jason Xiang, jxiang@wyeth.com¹, Lihren Chen, Lchen@wyeth.com¹, Nelson Huang, Nhuang@wyeth.com¹, Jim Li, JCLI@wyeth.com¹, Wei Li¹, Tarek Mansour, Mansout@wyeth.com¹, John C McKew, JMCKew@wyeth.com¹, Jill Nunez, JNunez@wyeth.com¹, Vipin Suri, Vsuri@wyeth.com², Tam May, MSTam@wyeth.com², Steve Tam, STam@wyeth.com¹, James F Tobin, JTobin@wyeth.com², Charlie Wu, CWu@wyeth.com¹, Yuzhe Xing, YXing@wyeth.com², Xin Xu, XXu@wyeth.com³, and Yanling Zhang, Yzhang@wyeth.com². (1) Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, (2) Cardiovascular and Metabolic Diseases, Wyeth Research, (3) Drug Safety and Metabolism, Wyeth Research

Glucocorticoid hormones are important chronic regulators of metabolism. Intracellular reactivation of inactive glucocorticoids has emerged as a key mechanism for regulation and amplification of glucocorticoid action. The reactivation is catalyzed by 11b-Hydroxysteroid Dehydrogenase type 1 (11b-HSD1). Mice over-expressing 11b-HSD1 in adipose or liver display a phenotype very similar to metabolic syndrome, while 11b-HSD1 knock out mice show a marked improvement in insulin sensitivity, lipid and cholesterol profiles. These data indicate that inhibitors of 11b-HSD1 could be novel therapeutics for patients with type 2 diabetes, obesity and metabolic syndrome.

Presented herein is the synthesis and SAR study of the b-keto sulfonamide series. In our screening strategy, a cell-based assay was used as our primary assay to evaluate analogs. The mechanism by which b-keto sulfonamides inhibit 11b-HSD1 activity was investigated.

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