Phosphinic acid-based MMP-13 inhibitors that spare MMP-1 and MMP-3

Bioorg Med Chem Lett. 2003 Jul 21;13(14):2331-6. doi: 10.1016/s0960-894x(03)00413-x.

Abstract

Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.

MeSH terms

  • Collagenases / chemistry
  • Indicators and Reagents
  • Isomerism
  • Matrix Metalloproteinase 1 / chemistry
  • Matrix Metalloproteinase 1 / drug effects*
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3 / chemistry
  • Matrix Metalloproteinase 3 / drug effects*
  • Matrix Metalloproteinase Inhibitors*
  • Phosphinic Acids / chemistry*
  • Phosphinic Acids / pharmacology*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Indicators and Reagents
  • Matrix Metalloproteinase Inhibitors
  • Phosphinic Acids
  • Protease Inhibitors
  • Collagenases
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1