Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11β-hydroxydehydrogenase 1 (11β-HSD1)

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6693-8. doi: 10.1016/j.bmcl.2011.09.058. Epub 2011 Sep 21.

Abstract

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism*
  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2 / drug therapy
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacokinetics
  • Isoquinolines / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoquinolines
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1