Chauvel E N, Coric P, Llorens-Cortès C, Wilk S, Roques B P, Fournié-Zaluski M C
Unité de Pharmacochimie Moléculaire et Structurale, U266 INSERM, URA D 1500 CNRS, Université René Descartes, UFR des sciences pharmaceutiques et biologiques, Paris, France.
J Med Chem. 1994 Apr 29;37(9):1339-46. doi: 10.1021/jm00035a014.
Aminopeptidase A (APA) and aminopeptidase N (APN) are two metallopeptidases which have been suggested to be involved in the enzymatic cascade of the renin-angiotensin system. APA liberates angotensin III from angiotensin II by releasing the N-terminal aspartate, and APN participates in the inactivation of angiotensin III. As the role of angiotensin III in the regulation of blood pressure in the central nervous system and at the periphery is controversial, it was of interest to develop selective and efficient inhibitors of APA. Starting from Glu-thiol(1), which was the first efficient APA inhibitor described, but however is equipotent on APA (Ki = 0.14 microM) and APN (Ki = 0.12 microM), beta-amino thiols bearing various carboxyalkyl chains have been synthesized and their inhibitory potencies measured on both purified enzymes. Compounds containing a carboxylated aromatic ring inhibited APA and APN with Ki values in the micromolar range but were slightly more active on APA. Conversely, inhibitors containing a cyclohexyl ring were more efficient on APN. Various modifications of the structure of Glu-thiol decreased inhibitory activity on both enzymes but increased the selectivity for APA, and compound 9d ((S)-4-amino-6-mercaptohexanoic acid) was 23 times more potent on APA (Ki = 2.0 microM) than on APN (Ki = 45 microM).
氨肽酶A（APA）和氨肽酶N（APN）是两种金属肽酶，有人认为它们参与肾素 - 血管紧张素系统的酶促级联反应。APA通过释放N端天冬氨酸从血管紧张素II中释放出血管紧张素III，而APN参与血管紧张素III的失活。由于血管紧张素III在中枢神经系统和外周血压调节中的作用存在争议，因此开发选择性高效的APA抑制剂很有意义。从Glu-硫醇（1）开始，它是首个被描述的高效APA抑制剂，但对APA（Ki = 0.14 microM）和APN（Ki = 0.12 microM）的效力相同，已合成了带有各种羧基烷基链的β-氨基硫醇，并测定了它们对两种纯化酶的抑制效力。含有羧化芳环的化合物对APA和APN的抑制作用，其Ki值在微摩尔范围内，但对APA的活性略高。相反，含有环己基环的抑制剂对APN更有效。Glu-硫醇结构的各种修饰降低了对两种酶的抑制活性，但增加了对APA的选择性，化合物9d（（S）-4-氨基-6-巯基己酸）对APA（Ki = 2.0 microM）的效力比对APN（Ki = 45 microM）高23倍。
