1. Academic Validation
  2. Synthesis of potent and orally efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016

Synthesis of potent and orally efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016

  • J Org Chem. 2011 Sep 2;76(17):7048-55. doi: 10.1021/jo200958a.
Zhao-Kui Wan 1 Eva Chenail Huan-Qiu Li Christopher Kendall Youchu Wang Stéphane Gingras Jason Xiang Walter W Massefski Tarek S Mansour Eddine Saiah
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research and Development, Pfizer Inc., 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA. zhao-kui.wan@pfizer.com
Abstract

Cortisol and the Glucocorticoid Receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11β-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11β-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.

Figures
Products