Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11[beta]-hydroxysteroid dehydrogenase type I

Indole-pyrrolidines were identified as inhibitors of 11[beta]-hydroxysteroid dehydrogenase type 1 (11[beta]-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC50 potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11[beta]-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11[beta]-HSD1 (IC50 < 1 AmM) in a cellular model (3T3L1 adipocytes)