N.alpha.-(O,O'-Diphenoxyphosphoryl)-L-alanyl-L-proline, N.alpha.-[O,O'-bis(4-nitrophenoxy)phosphoryl]-L-alanyl-L-proline and N.alpha.-[P-(2-phenylethyl)-O-phenoxyphosphoryl]-L-alanyl-L-proline: releasers of potent inhibitors of angiotensin converting enzyme at physiological pH and temperature

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Abstract
The rate of loss of phenol or 4-nitrophenol from Na-(diphenoxyphosphoryl)-L-alanyl-L-proline (2), N.alpha.-[bis(4-nitrophenoxy)phosphoryl]-L-alanyl-L-proline (5) and N.alpha.[(2-phenylethyl)phenoxyphosphoryl]-L-alanyl-L-proline (12) was determined spectrophotometrically at pH 7.5 and 37.degree. C in both Tris and phosphate buffers. These moderately potent inhibitors of angiotensin converting enzyme (Ki > 0.8 .mu.M) all hydrolyze, losing 1 mol of phenol to yield highly potent inhibitors (Ki = 0.5-18 nM). The half-times for loss of 1 mol of phenol in Tris buffer are 22 days (2), 3, 4 h (5), and 21 days (12). The half-times in phosphate buffer were not significantly different. The mono(2-nitrophenoxy)ester 6 (Ki = 18 nM) loses its 1 mol of nitrophenol with a half-time of 35 h to yield Na-phosphoryl-L-alanyl-L-proline 16 (Ki = 1.4 nM), which hydrolyzes at the P-N bond with a half-time of 2.2 h. Hydrolysis of the P-N bond in 2 and 12 was not observed during the time course of the kinetic experiments. The two phosphoramidate diesters 2 and 5 and the phosphonamidate monoester 12 thus release powerful inhibitors of angiotensin converting enzyme with a known time course at physiological pH and temperature in vitro. A time-dependent increase in inhibitory potency against converting enzyme that paralleled the kinetics of phenyl ester hydrolysis was confirmed in vitro.

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