Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors

J Med Chem. 2001 Oct 11;44(21):3347-50. doi: 10.1021/jm015533c.

Abstract

A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.

MeSH terms

  • Administration, Oral
  • Animals
  • Asparagine / analogs & derivatives
  • Asparagine / chemical synthesis*
  • Asparagine / chemistry
  • Asparagine / pharmacokinetics
  • Asparagine / pharmacology
  • Biological Availability
  • Dogs
  • Drug Design
  • Endopeptidases / chemistry
  • Endopeptidases / metabolism*
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / pharmacology
  • Matrix Metalloproteinase 1 / chemistry
  • Matrix Metalloproteinase 2 / chemistry
  • Matrix Metalloproteinase 8 / chemistry
  • Matrix Metalloproteinase 9 / chemistry
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Hydroxamic Acids
  • N-hydroxy-2-(cyclopropylmethylamino)-4-((2-hydroxyindan-1-yl)amino)-3-((3-hydroxyphenyl)methyl)-4-oxobutanamide
  • Protease Inhibitors
  • Asparagine
  • Endopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 1
  • aggrecanase