Inhibitors of the bradykinin-degrading enzyme, aminopeptidase P

Aminopeptidase P inactivates bradykinin by hydrolyzing the bond [1]. This enzyme is a metallo-aminopeptidase with specificity for proline in the penultimate position. An inhibitor of this enzyme was synthesized and called apstatin (N-[(2S,3R)-3amino-2-hydroxy-4-phenylbutanoyl]-L-Pro-L-Pro-L-Ala-NH2) [2]. The N-terminal residue of apstatin was designed to chelate the active site through the amino and hydroxyl functions. The remaining residues were designed to accommodate the primary and secondary specificity requirements. Apstatin has an of for human membranebound aminopeptidase P. Apstatin together with an angiotensin converting enzyme inhibitor can completely block bradykinin degradation in the rat pulmonary and coronary circulations [2,3]. Apstatin can potentiate the vasodepressor response to intravenously-administered bradykinin and can reduce blood pressure in rats made hypertensive by aortic coarctation [4]. Apstatin can also significantly reduce cardiac ischemia/reperfusion damage as well as decrease reperfusion-induced ventricular fibrillation in the isolated rat heart [5]. The antihypertensive and cardioprotective effects of apstatin are blocked by a bradykinin receptor antagonist, suggesting that apstatin’s effects are due to potentiation of endogenously-formed bradykinin. In order to delineate the structural requirements for aminopeptidase P inhibition, 15 apstatin analogs were synthesized and tested for their ability to inhibit membrane-bound aminopeptidase P from human, monkey, rat, and bovine lung. Data for the human enzyme are described.