A library of novel hydroxamic acids targeting the metallo-protease family: design, parallel synthesis and screening

Bioorg Med Chem. 2007 Jan 1;15(1):63-76. doi: 10.1016/j.bmc.2006.10.010. Epub 2006 Oct 12.

Abstract

We report here the design and parallel synthesis of 217 compounds based on a malonic-hydroxamic acid template. These compounds are obtained via a two-step solution-phase procedure. The set of diverse building-blocks used makes this strategy suitable for the search of inhibitors of various metallo-proteases and for the investigation of the biological role of new metallo-proteases. As a proof of concept, we screened this library on Neutral Aminopeptidase (APN; EC 3.4.11.2), the prototypal enzyme of the M1 family. Several submicromolar inhibitors were identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / chemistry
  • Animals
  • Combinatorial Chemistry Techniques / methods*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Kidney / enzymology
  • Microsomes / enzymology
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swine
  • Zinc / chemistry

Substances

  • Hydroxamic Acids
  • Protease Inhibitors
  • Aminopeptidases
  • Zinc