Structure-based library design and the discovery of a potent and selective mast cell β-tryptase inhibitor as an oral therapeutic agent

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1049-54. doi: 10.1016/j.bmcl.2011.11.119. Epub 2011 Dec 7.

Abstract

A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to β-tryptase and does not exist for other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against other proteases in the same family. A member of this library was found to be a potent and selective β-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation.

MeSH terms

  • Administration, Oral
  • Animals
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mast Cells / enzymology*
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Recombinant Proteins / antagonists & inhibitors
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Tryptases / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Recombinant Proteins
  • Small Molecule Libraries
  • Tryptases