A new class of potent, slowly reversible dehydropeptidase inhibitors.
Dehydrodipeptide analogs whose scissile carboxamide has been replaced with a PO(OH)CH2 group have been found to be potent inhibitors of the zinc protease dehydrodipeptidase 1 (DHP-1, renal dipeptidase, EC 3.4.13.11). The best of these inhibitors, compound 25 (Ki = 0.52 nM), is two hundred times more potent than cilastatin 2 which is used clinically as a component of the broad-spectrum antibiotic combination Primaxin. Compound 25 is a tight binding inhibitor exhibiting slow binding kinetics with a remarkably slow off rate from DHP-1 (half life greater than 8 hours). The kinetics of its binding are consistent with a simple on-off mechanism whereas the less active D-enantiomer 26 appears to bind in an initial loose complex with the enzyme which slowly rearranges to a tighter complex (Ki = 83 nM).
Parsons
W H
WH
Merck Sharp and Dohme Research Laboratories, Rahway, N.J. 07065.
Hajdu
R
R
Schoen
W R
WR
Combs
P L
PL
Sundelof
J
J
Patchett
A A
AA
D000818:Animals; D015377:Cilastatin / Q000737:chemistry / Q000494:pharmacology; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D015394:Molecular Structure; D013379:Substrate Specificity; D013552:Swine
D015377:Cilastatin; D004150:Dipeptidases; C038937:dipeptidase