Discovery and Biological Evaluation of Potent and Orally Active Human 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Type 2 Diabetes Mellitus.

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.

Sequential coupling of zincated hydrazone, alkenylboronate, and electrophile that creates several contiguous stereogenic centers.

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.