- Synthesis of potent and orally efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016
-
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.
- Wan, Zhao-Kui,Chenail, Eva,Li, Huan-Qiu,Kendall, Christopher,Wang, Youchu,Gingras, Stephane,Xiang, Jason,Massefski, Walter W.,Mansour, Tarek S.,Saiah, Eddine
-
p. 7048 - 7055
(2011/10/30)
-
- 11-BETA HSD1 1NHIBITORS
-
This invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof). Formula I is provided below: formula (I) R1, R2, R3, R4, R5, R6, R7, R8, R9, and A can be as defined anywhere herein
- -
-
Page/Page column 79-80
(2010/12/29)
-
- Piperazine sulfonamides as potent, selective, and orally available 11β-hydroxysteroid dehydrogenase type 1 inhibitors with efficacy in the rat cortisone-induced hyperinsulinemia model
-
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11β-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11β-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11β-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.
- Xiang, Jason,Wan, Zhao-Kui,Li, Huan-Qiu,Ipek, Manus,Binnun, Eva,Nunez, Jill,Chen, Lihren,McKew, John C.,Mansour, Tarek S.,Xu, Xin,Suri, Vipin,Tam, May,Xing, Yuzhe,Li, Xiangping,Hahm, Seung,Tobin, James,Saiah, Eddine
-
supporting information; experimental part
p. 4068 - 4071
(2009/05/30)
-