- 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
-
body text
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 48-49
(2010/12/29)
-
- Efficacious 11β-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model
-
Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11β-hydroxysteroid dehydrogenase type I (11β-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11α-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11β-HSD1 inhibition may be a valid target for the treatment of diabetes.
- Wan, Zhao-Kui,Chenail, Eva,Xiang, Jason,Li, Huan-Qiu,Ipek, Manus,Bard, Joel,Svenson, Kristine,Mansour, Tarek S.,Xu, Xin,Tian, Xianbin,Suri, Vipin,Hahm, Seung,Xing, Yuzhe,Johnson, Christian E.,Li, Xiangping,Qadri, Ariful,Panza, Darrell,Perreault, Mylene,Tobin, James F.,Saiah, Eddine
-
experimental part
p. 5449 - 5461
(2010/02/28)
-
- 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)
-
- 11-BETA HSD1 INHIBITORS
-
This invention relates to inhibiting 11βHSD1.
- -
-
Page/Page column 182; 193-194
(2008/06/13)
-