A new class of potent, slowly reversible dehydropeptidase inhibitors
Parsons, W.H.; Hajdu, R.; Schoen, W.R.; Combs, P.L.; Sundelof, J.; Patchett, A.A.
Biochemistry International 23(6): 1107-1115
1991
ISSN/ISBN: 0158-5231 PMID: 1953807 Document Number: 603
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).
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