Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4250-3. doi: 10.1016/j.bmcl.2015.07.097. Epub 2015 Aug 5.

Abstract

The adamantane scaffold is found in several marketed drugs and in many investigational 11β-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred over the substitution at C-1 and is necessary for potency at human 11β-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11β-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features.

Keywords: 11β-HSD1 inhibitors; Adamantane; Drug discovery; Molecular modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Adamantane / chemistry*
  • Adamantane / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Oxygen / chemistry*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Adamantane
  • Oxygen