Synthesis of Potent and Orally Efficacious 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor HSD-016

• Published in: Journal of organic chemistry Vol. 76; no. 17; pp. 7048 - 7055
• Main Authors: Wan, Zhao-Kui, Chenail, Eva, Li, Huan-Qiu, Kendall, Christopher, Wang, Youchu, Gingras, Stéphane, Xiang, Jason, Massefski, Walter W, Mansour, Tarek, S, Saiah, Eddine
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.09.2011; Amer Chemical Soc
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - chemical synthesis; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - chemistry; Administration, Oral; Alicyclic compounds, terpenoids, prostaglandins, steroids; Chemistry; Chemistry, Organic; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Molecular Structure; Organic chemistry; Physical Sciences; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Preparations and properties; Propanols - chemical synthesis; Propanols - chemistry; Propanols - pharmacology; Science & Technology; Steroids; SELECTIVE-INHIBITION; KETONES; ENANTIOSELECTIVE TRIFLUOROMETHYLATION; TERTIARY ALCOHOLS; ASYMMETRIC TRIFLUOROMETHYLATION; VISCERAL OBESITY; DISCOVERY; Type 2 diabetes; Steroid; Nitrogen heterocycle; Isozyme; Chiral compound; Selectivity; Hydrocortisone; Oxygen heterocycle; Glucocorticoid; Chemical reduction; Asymmetric synthesis; Tertiary alcohol; 11β-Hydroxysteroid dehydrogenase; Chemical synthesis; Biological receptor; Catalytic reaction; Enzyme; Enzyme inhibitor; In vivo; Sharpless dihydroxylation; Epoxide; Organic fluorine compounds; Inhibitor; Oxidoreductases; Piperazine derivatives
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo200958a

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.