Development of matrix metalloproteinase-13 inhibitors - A structure-activity/structure-property relationship study

Bioorg Med Chem. 2018 Oct 1;26(18):4984-4995. doi: 10.1016/j.bmc.2018.08.020. Epub 2018 Aug 20.

Abstract

A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 μM, and a permeability coefficient greater than 20 × 10-6 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (Cmax = 56.8 μM, T1/2 (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model.

Keywords: In vitro and in vivo pharmacokinetics; Matrix metalloproteinase 13; Microsomal stability; Permeability; Solubility; Structure-activity relationship; Structure-property relationship.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Half-Life
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Matrix Metalloproteinase 13 / drug effects*
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacokinetics
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Mice
  • Microsomes, Liver / metabolism
  • Models, Animal
  • Rats
  • Solubility
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 13