1. Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes
- Author
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Tarek S. Mansour, Mylene Perreault, Joel Bard, Eva Chenail, Xianbin Tian, James F. Tobin, Xiangping Li, Jason Shaoyun Xiang, Zhao-Kui Wan, Xin Xu, Manus Ipek, Darrell Panza, Kristine Svenson, Huan-Qiu Li, Eddine Saiah, Ariful Qadri, Vipin Suri, Mengmeng Wang, Christian E. Johnson, and Seung Hahm
- Subjects
endocrine system ,medicine.medical_specialty ,business.industry ,Insulin ,medicine.medical_treatment ,Organic Chemistry ,Sulfonamide (medicine) ,Type 2 diabetes ,Pharmacology ,medicine.disease ,Biochemistry ,Glucocorticoid receptor ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Drug Discovery ,Medicine ,Cortisone ,Metabolic syndrome ,business ,hormones, hormone substitutes, and hormone antagonists ,Glucocorticoid ,medicine.drug - Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-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-activity relationship of a series of piperazine sulfonamide-based 11β-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 11β-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.
- Published
- 2012