A new 4-(2-methylquinolin-4-ylmethyl)phenyl P1' group for the beta-amino hydroxamic acid derived TACE inhibitors

Bioorg Med Chem Lett. 2007 Apr 1;17(7):1865-70. doi: 10.1016/j.bmcl.2007.01.041. Epub 2007 Jan 24.

Abstract

A new P1' group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1' group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different beta-aminohydroxamic acid cores provided compound 18, which demonstrated potent porcine TACE (p-TACE) and human whole blood activity, excellent PK properties, and good selectivity against a variety of MMPs.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM Proteins / blood
  • ADAM17 Protein
  • Animals
  • Chemistry, Pharmaceutical / methods*
  • Dogs
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydroxamic Acids / chemistry*
  • Inhibitory Concentration 50
  • Models, Chemical
  • Molecular Conformation
  • Oxygen / chemistry
  • Rats
  • Structure-Activity Relationship
  • Swine

Substances

  • Enzyme Inhibitors
  • Hydroxamic Acids
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, rat
  • Oxygen