Discovery and optimization of arysulfonamide as a novel class of 11beta-HSD1 inhibitors

MEDI 55

Daqing Sun, daqings@amgen.com1, Michael DeGraffenreid1, Xiao He1, Juan Jaen1, Jay P. Powers, jppowers@amgen.com1, Xuelei Yan1, Yongmei Di2, Hua Tu2, Stefania Ursu2, Ji Ma3, Shichang Miao3, Liang Tang3, Qiuping Ye3, Athena Sudom4, and Zhulun Wang4. (1) Department of Chemistry Research & Discovery, Amgen, Inc, 1120 Veterans Blvd., South San Francisco, CA 94080, (2) Department of Biology, Amgen, Inc, 1120 Veterans Blvd., South San Francisco, CA 94080, (3) Department of PKDM, Amgen, Inc, 1120 Veterans Blvd., South San Francisco, CA 94080, (4) Department of Structural Biology, Amgen, Inc, 1120 Veterans Blvd., South San Francisco, CA 94080
11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) is a key enzyme that converts the inactive glucocorticoid cortisone to the active form (cortisol) in specific tissue, notably liver, adipose, and brain, and therefore regulates tissue-specific glucocorticoid level. Given its role in tissue-specific glucocorticoid action and the link of the hepatic and adipose glucocorticoid action to insulin resistance and dyslipidemia, 11 beta-HSD1 inhibition is a promising strategy to improve insulin sensitivity and treat type II diabetes. In this presentation, we will disclose the discovery of a series of arysulfonamides (I), a novel class of 11 beta-HSD1 inhibitors that shows potent and selective inhibition of both mouse and human 11 beta-HSD1 in different cells. We will also present our efforts to advance the SAR and improve selectivity by reducing p450 and hERG activities. These efforts resulted in compound (II), which exhibits superior potency, excellent oral bioavailability and efficacy in a cyno ex vivo model.

 

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

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Medicinal Chemistry

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