Novel peptidyl phosphorus derivatives as inhibitors of human calpain I

J Med Chem. 1998 Sep 24;41(20):3912-6. doi: 10.1021/jm980325e.

Abstract

Dipeptidyl phosphorus compounds were synthesized as potential bioisosteric mimics of peptide alpha-ketoesters and alpha-ketoacids. alpha-Ketophosphonate Cbz-Leu-Leu-P(O)(OCH3)2 (1b), containing an alpha-ketoester bioisostere, inhibits human calpain I with an IC50 = 0.43 microM. The potency of 1b compares very favorably with that of alpha-ketoester Cbz-Leu-Leu-CO2Et (IC50 = 0.60 microM). Monomethyl ketophosphonate Cbz-Leu-Leu-P(O)(OH)(OCH3) (1a, IC50 = 5.2 microM), an alpha-ketoacid mimic, is less potent. Dibutyl and dibenzyl alpha-ketophosphonates 1c,e,f are much less potent calpain inhibitors than dimethyl alpha-ketophosphonate 1b. alpha-Ketophosphinate 1g (IC50 = 0.37 microM) and alpha-ketophosphine oxide 1h (IC50 = 0.35 microM) are also potent calpain inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calpain / antagonists & inhibitors*
  • Dipeptides* / chemical synthesis
  • Dipeptides* / chemistry
  • Dipeptides* / pharmacology
  • Humans
  • Organophosphonates* / chemical synthesis
  • Organophosphonates* / chemistry
  • Organophosphonates* / pharmacology
  • Oxides* / chemical synthesis
  • Oxides* / chemistry
  • Oxides* / pharmacology
  • Phosphines* / chemical synthesis
  • Phosphines* / chemistry
  • Phosphines* / pharmacology
  • Phosphinic Acids* / chemical synthesis
  • Phosphinic Acids* / chemistry
  • Phosphinic Acids* / pharmacology
  • Recombinant Proteins / antagonists & inhibitors
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Organophosphonates
  • Oxides
  • Phosphines
  • Phosphinic Acids
  • Recombinant Proteins
  • Calpain