Discovery of non-competitive thrombin inhibitor derived from competitive tryptase inhibitor skeleton: Shift in molecular recognition resulted from skeletal conversion of carboxylate into phosphonate

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3676-80. doi: 10.1016/j.bmcl.2015.06.039. Epub 2015 Jun 17.

Abstract

A novel series of terminal and internal phosphonate esters based on our previously developed aryl carboxylate-type tryptase selective inhibitor 1 was synthesized. The potency of these synthesized compounds was assessed in vitro with an enzyme inhibition assay using three available serine proteases, that is, tryptase, trypsin, and thrombin. The internal phosphonate derivative 6 showed potent thrombin inhibitory activity with an IC50 value of 1.0 μM, whereas it exhibited no or only weak tryptase and trypsin inhibition at 10 μM. The Lineweaver-Burk plot analysis indicates that the inhibition pattern of thrombin with 6 is non-competitive in spite of the fact that the lead carboxylate compound 1 is competitive inhibitor. Therefore, the skeletal conversion of the carboxylate into a phosphonate alters the mode of molecular recognition of these inhibitors by thrombin.

Keywords: Aryl phosphonate ester; Non-competitive inhibitor; Serine protease; Thrombin; Tryptase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticoagulants / chemistry
  • Anticoagulants / pharmacology
  • Antithrombins / chemistry*
  • Antithrombins / pharmacology*
  • Carboxylic Acids / chemistry
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Drug Discovery
  • Drug Evaluation, Preclinical / methods
  • Inhibitory Concentration 50
  • Organophosphonates / chemistry
  • Structure-Activity Relationship
  • Tryptases / antagonists & inhibitors

Substances

  • Anticoagulants
  • Antithrombins
  • Carboxylic Acids
  • Organophosphonates
  • Tryptases