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Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes
- Publication Year :
- 2012
- Publisher :
- American Chemical Society, 2012.
-
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.
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....ac55ea3454d8d6acc241eb07df394729