Optimization of orally bioavailable alkyl amine renin inhibitors

Bioorg Med Chem Lett. 2010 Jan 15;20(2):694-9. doi: 10.1016/j.bmcl.2009.11.066. Epub 2009 Dec 1.

Abstract

Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.

MeSH terms

  • Administration, Oral
  • Amines / chemical synthesis
  • Amines / chemistry*
  • Amines / pharmacokinetics
  • Animals
  • Binding Sites
  • Blood Pressure / drug effects
  • Carbamates / chemical synthesis
  • Carbamates / chemistry*
  • Carbamates / pharmacokinetics
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Haplorhini
  • Humans
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Rats
  • Rats, Transgenic
  • Renin / antagonists & inhibitors*
  • Renin / blood
  • Renin / metabolism
  • Structure-Activity Relationship

Substances

  • Amines
  • Carbamates
  • Enzyme Inhibitors
  • Piperidines
  • Renin