title: Synthesis of potent and orally efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016.
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.
authors: Pfizer Worldwide Research and Development, Pfizer Inc., 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA. zhao-kui.wan@pfizer.com
authors: Zhao-Kui
authors: ZK
authors: Wan
authors: Eva
authors: E
authors: Chenail
authors: Huan-Qiu
authors: HQ
authors: Li
authors: Christopher
authors: C
authors: Kendall
authors: Youchu
authors: Y
authors: Wang
authors: Stéphane
authors: S
authors: Gingras
authors: Jason
authors: J
authors: Xiang
authors: Walter W
authors: WW
authors: Massefski
authors: Tarek S
authors: TS
authors: Mansour
authors: Eddine
authors: E
authors: Saiah
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D000284:Administration, Oral; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020005:Propanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D020005:Propanols; C569679:(R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1