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

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5909-14. doi: 10.1016/j.bmcl.2012.07.070. Epub 2012 Jul 31.

Abstract

Indole-pyrrolidines were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11β-HSD1 (IC(50)<1μM) in a cellular model (3T3L1 adipocytes).

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemistry*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Pyrrolidines / chemistry*
  • Structure-Activity Relationship

Substances

  • 7-azaindole dimer
  • Amides
  • Enzyme Inhibitors
  • Indoles
  • Pyrrolidines
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • pyrrolidine