ABSTRACT
We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Triazoles/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , HEK293 Cells , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Male , Mice , Mice, Obese , Molecular Structure , Structure-Activity Relationship , Triazoles/administration & dosage , Triazoles/chemistryABSTRACT
A zincated N,N-dimethylhydrazone of a ketone undergoes stereospecific syn addition to E- or Z-alkenylboronate to generate a gamma-Zn/B dimetallic intermediate, which reacts with a carbon electrophile to give a gamma-borylhydrazone in good yield with excellent diastereoselectivity, creating two to four contiguous stereogenic centers in a one-pot reaction.
