title: Novel peptidyl phosphorus derivatives as inhibitors of human calpain I.
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.
authors.affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380-4245, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tao
authors.forename: R
authors.initials: R
authors.lastname: Bihovsky
authors.forename: G J
authors.initials: GJ
authors.lastname: Wells
authors.forename: J P
authors.initials: JP
authors.lastname: Mallamo
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010087:Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010720:Phosphines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D063065:Organophosphonates; D010087:Oxides; D010720:Phosphines; D010721:Phosphinic Acids; D011994:Recombinant Proteins; D002154:Calpain