4-(Phenylsulfonamidomethyl)benzamides as potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1 with efficacy in diabetic ob/ob mice.
Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) have considerable potential as treatments for type 2 diabetes. Presented herein are the syntheses, structure-activity relationships, and efficacy evaluation of 4-(phenylsulfonamidomethyl)benzamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5, we have identified potent and selective 11beta-HSD1 inhibitors, such as 11n, which demonstrated improved glycemic control, decreased serum lipids, and enhanced insulin sensitivity when dosed ip in diabetic ob/ob mice.
Zhang
Xu
X
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Zhou
Zhou
Z
Yang
Huaiyu
H
Chen
Junhua
J
Feng
Ying
Y
Du
Lili
L
Leng
Ying
Y
Shen
Jianhua
J
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D051379:Mice; D008820:Mice, Obese; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D001549:Benzamides; D001786:Blood Glucose; D013449:Sulfonamides; C037689:benzamide; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1