Solid-phase synthesis of a combinatorial array of 1,3-bis(acylamino)-2-butanones, inhibitors of the cysteine proteases cathepsins K and L

J Comb Chem. 1999 May-Jun;1(3):207-15. doi: 10.1021/cc9800374.

Abstract

To more rapidly prepare members of the 1,3-bis(acylamino)-2-butanone class of cysteine protease inhibitors, a solid-phase synthesis was developed. 1-Azido-3-amino-2,2-dimethoxybutane (4), which has the two amino groups differentiated and the ketone protected as a a ketal, served as a surrogate for the 1,3-diamino-2-butanone core. Amine (4) was coupled to the BAL-resin-linked carboxylic acids derived from alpha-amino acid esters. Evaluation of a small combinatorial array by measuring inhibition constants (Ki,appS) against cathepsins K, L, and B provided some structure-activity relationship trends with respect to selectivity and potency. Novel, potent inhibitors of cathepsins K and L were identified.

MeSH terms

  • Butanones / chemical synthesis*
  • Butanones / chemistry
  • Butanones / pharmacology
  • Cathepsin K
  • Cathepsin L
  • Cathepsins / antagonists & inhibitors*
  • Combinatorial Chemistry Techniques / methods*
  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Design
  • Endopeptidases*
  • Kinetics
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • 1,3-bis(acylamino)-2-butanone
  • Butanones
  • Cysteine Proteinase Inhibitors
  • Cathepsins
  • Endopeptidases
  • Cysteine Endopeptidases
  • Cathepsin L
  • Cathepsin K