Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury

J Med Chem. 2013 Mar 28;56(6):2568-80. doi: 10.1021/jm400014c. Epub 2013 Mar 8.

Abstract

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / pharmacokinetics
  • Amino Acids / pharmacology*
  • Amino Acids / therapeutic use
  • Animals
  • Arginase / antagonists & inhibitors*
  • Arginase / chemistry
  • Boron Compounds / chemistry*
  • Boron Compounds / pharmacokinetics
  • Boron Compounds / pharmacology*
  • Boron Compounds / therapeutic use
  • CHO Cells
  • Caproates / chemistry*
  • Caproates / pharmacokinetics
  • Caproates / pharmacology*
  • Caproates / therapeutic use
  • Cricetinae
  • Cricetulus
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Male
  • Models, Molecular
  • Myocardial Reperfusion Injury / drug therapy*
  • Protein Conformation
  • Rats
  • Structure-Activity Relationship

Substances

  • 2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid
  • Amino Acids
  • Boron Compounds
  • Caproates
  • Enzyme Inhibitors
  • hexanoic acid
  • ARG1 protein, human
  • ARG2 protein, human
  • Arginase