trans-(3S,4S)-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part I: prime site exploration using an amino linker

Bioorg Med Chem Lett. 2015 Apr 15;25(8):1782-1786. doi: 10.1016/j.bmcl.2015.02.039. Epub 2015 Feb 21.

Abstract

Recently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g., 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2.

Keywords: Direct renin inhibitor; Hypertension; Pyrrolidine; Structure guided drug design.

MeSH terms

  • Aspartic Acid Proteases / antagonists & inhibitors
  • Aspartic Acid Proteases / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Half-Life
  • Humans
  • Isomerism
  • Molecular Dynamics Simulation
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism
  • Renin / antagonists & inhibitors*
  • Renin / metabolism
  • Structure-Activity Relationship

Substances

  • Protease Inhibitors
  • Pyrrolidines
  • Aspartic Acid Proteases
  • Renin
  • pyrrolidine