Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes
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- 作者：Zhao-Kui Wan ; Eva Chenail ; Huan-Qiu Li ; Manus Ipek ; Jason Xiang ; Vipin Suri ; Seung Hahm ; Joel Bard ; Kristine Svenson ; Xin Xu ; Xianbin Tian ; Mengmeng Wang ; Xiangping Li ; Christian E. Johnson ; Ariful Qadri ; Darrell Panza ; Mylene Perreault ; Tarek S. Mansour ; James F. Tobin ; Eddine Saiah
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：January 10, 2013
- 年：2013
- 卷：4
- 期：1
- 页码：118-123
- 全文大小：365K
- 年卷期：v.4,no.1(January 10, 2013)
- ISSN：1948-5875
文摘
11尾-Hydroxysteroid dehydrogenase type 1 (11尾-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure鈥揳ctivity relationship of a series of piperazine sulfonamide-based 11尾-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11尾-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.