Novel Peptidyl Phosphorus Derivatives as Inhibitors of Human Calpain I

• Published in: Journal of medicinal chemistry 1998-09, Vol.41 (20), p.3912-3916
• Main Authors: Tao, Ming, Bihovsky, Ron, Wells, Gregory J, Mallamo, John P
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Calpain - antagonists & inhibitors; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Humans; Medical sciences; Neuropharmacology; Neuroprotective agent; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Oxides - chemical synthesis; Oxides - chemistry; Oxides - pharmacology; Pharmacology. Drug treatments; Phosphines - chemical synthesis; Phosphines - chemistry; Phosphines - pharmacology; Phosphinic Acids - chemical synthesis; Phosphinic Acids - chemistry; Phosphinic Acids - pharmacology; Recombinant Proteins - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980325e

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