ABSTRACT
Indole-pyrrolidines were identified as inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-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 IC(50) 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 11ß-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11ß-HSD1 (IC(50)<1µM) in a cellular model (3T3L1 adipocytes).
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Amides/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Pyrrolidines/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Amides/chemical synthesis , Amides/chemistry , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Mice , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Spiro-carboxamides were identified as inhibitors of 11beta-hydroxysteroid-dehydrogenase type 1 by high-throughput screening. Structure-based drug design was used to optimise the initial hit yielding a sub-nanomolar IC(50) inhibitor (0.5nM) on human 11beta-HSD1 with a high binding efficiency index (BEI of 32.7) which was selective against human 11beta-HSD2 (selectivity ratio>200000).
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Amides/chemistry , Enzyme Inhibitors/chemistry , Spiro Compounds/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Amides/pharmacology , Binding Sites , Computer Simulation , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Benzylamides of pentanedioic acid were identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC(50)s on the 11beta-HSD1 human isoform. The hydroxy adamantyl amide lead compound was selective against 11beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio >1000) and displayed good inhibition of 11beta-HSD1 (IC(50)<0.1microM) in a cellular model (3T3L1 adipocytes).
