Elliott R L, Marks N, Berg M J, Portoghese P S
J Med Chem. 1985 Sep;28(9):1208-16. doi: 10.1021/jm00147a015.
The effectiveness of phosphonamidate peptide analogues as inhibitors of rat kidney or human brain metalloendopeptidase (enkephalinase, E.C. 3.4.24.11) and angiotensin-converting enzyme (ACE, 3.4.14.1) has been explored with a series of enkephalin analogues in which the scissile Gly3-Phe4 amide bond has been replaced with a phosphonamidate moiety. These compounds exhibited good inhibitory potency against enkephalinase with several of the analogues having Ki values in the submicromolar range as contrasted to micromolar or higher toward ACE. Within a series of [(N-acylamino)methyl] phosphonamidates there was a dramatic decrease in inhibitory activity against enkephalinase as the N-acyl moiety was substituted with larger, more hydrophobic acyl groups. Likewise, the inhibitory activity of the [(N-acylamino)methyl] phosphonamidates against ACE was attenuated by larger phenylalkyl acyl functionalities, although not to the same degree as against enkephalinase. However, phosphonamidate pentapeptide analogues of (Leu)enkephalin and (D-Ala2,D-Leu5)enkephalin showed good inhibitory potency against both enzymes. Interestingly, these two (Leu)enkephalin phosphonamidate analogues were completely inactive in the electrically stimulated guinea pig ileum and mouse vas deferens preparations. Conformational factors that may be involved in this inactivity are discussed.
已经用一系列脑啡肽类似物探究了膦酰胺肽类似物作为大鼠肾脏或人脑金属内肽酶（脑啡肽酶，E.C. 3.4.24.11）和血管紧张素转换酶（ACE，3.4.14.1）抑制剂的有效性，其中可裂解的Gly3 - Phe4酰胺键已被膦酰胺部分取代。这些化合物对脑啡肽酶表现出良好的抑制效力，几种类似物的Ki值在亚微摩尔范围内，而对ACE的Ki值为微摩尔或更高。在一系列[（N - 酰基氨基）甲基]膦酰胺中，随着N - 酰基部分被更大、更疏水的酰基取代，对脑啡肽酶的抑制活性急剧下降。同样，[（N - 酰基氨基）甲基]膦酰胺对ACE的抑制活性也因更大的苯烷基酰基官能团而减弱，尽管程度不如对脑啡肽酶的抑制。然而，亮脑啡肽和（D - Ala2，D - Leu5）亮脑啡肽的膦酰胺五肽类似物对这两种酶都表现出良好的抑制效力。有趣的是，这两种亮脑啡肽膦酰胺类似物在电刺激的豚鼠回肠和小鼠输精管制剂中完全无活性。讨论了可能与这种无活性有关的构象因素。
