新型非肽类氨基肽酶A抑制剂的合成及其体外活性
Synthesis and in vitro activities of new non-peptidic APA inhibitors.
作者信息
Inguimbert N, Coric P, Dhotel H, Bonnard E, Llorens-Cortes C, Mota N, Fournié-Zaluski M-C, Roques B-P
机构信息
Laboratoire de Pharmacologie Chimique et Génétique, Université René Descartes Paris V, UFR des Sciences Pharmaceutiques et Biologiques, INSERM U 640, CNRS UMR 8151, 4, avenue de l'observatoire, 75270 Paris Cedex 06, France.
出版信息
J Pept Res. 2005 Feb;65(2):175-88. doi: 10.1111/j.1399-3011.2004.00211.x.
Aminopeptidase A (APA) is involved in the maturation of angiotensin III, a peptide which seems to be implicated in blood pressure regulation at the brain level. Therefore APA inhibitors are potential new antihypertensive agents with possible novel applications. With the aim of enhancing the bioavailability and potency of EC 33, the APA inhibitor (Ki = 300 nM) initially used in the earlier studies, we have synthesized new non-peptidic inhibitors able to interact with the S1 and S'1 subsites of the targeted enzyme. Compound 10a, (3S,4S)-3-amino-4-mercapto-6-phenyl-hexane-1-sulfonic acid was obtained using an asymmetric synthesis. Inhibitor 10a exhibits a Ki value of 30 nm.
氨肽酶A（APA）参与血管紧张素III的成熟过程，血管紧张素III是一种似乎在大脑水平参与血压调节的肽。因此，APA抑制剂是具有潜在新应用的新型抗高血压药物。为了提高早期研究中最初使用的APA抑制剂EC 33（Ki = 300 nM）的生物利用度和效力，我们合成了能够与目标酶的S1和S'1亚位点相互作用的新型非肽类抑制剂。化合物10a，即(3S,4S)-3-氨基-4-巯基-6-苯基己烷-1-磺酸，通过不对称合成获得。抑制剂10a的Ki值为30 nm。
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