Peet N P, Burkhart J P, Angelastro M R, Giroux E L, Mehdi S, Bey P, Kolb M, Neises B, Schirlin D
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
J Med Chem. 1990 Jan;33(1):394-407. doi: 10.1021/jm00163a063.
Comparison of MeO-Suc-Val-Pro-Phe-CO2Me (29) and MeO-Suc-Ala-Ala-Pro-Phe- CO2Me (25) with their corresponding trifluoromethyl ketones 9a and 9b, respectively, in rat and human neutrophil cathepsin G assays showed the alpha-keto esters to be more potent inhibitors. Likewise, Ac-Pro-Ala-Pro-Ala-CO2Me (21) was more potent than its corresponding trifluoromethyl ketone (9c) in both porcine pancreatic elastase and human neutrophil elastase assays. Within a set of Ala-Ala-Pro-Val-CF3 elastase inhibitors, the carbobenzyloxy (Cbz) N-protecting group conferred greater potency as a P5 site recognition unit for elastase than did dansyl, methoxysuccinyl, or tert-butyloxycarbonyl. Initial inhibition of elastase was greater when trifluoromethyl ketone 9f was added from a stock solution of dimethyl sulfoxide than when it had been buffer-equilibrated prior to assay, which suggests that the nonhydrated ketone is the more effective form of the inhibitor. The most potent elastase inhibitor we report is Na-(Ad-SO2)-N epsilon-(MeO-Suc)Lys-Pro-Val-CF3 (16) which has a Ki of 0.58 nM.
在大鼠和人类中性粒细胞组织蛋白酶G检测中，分别将甲氧基琥珀酰缬氨酸-丙氨酸-脯氨酸-苯丙氨酸甲酯（29）和甲氧基琥珀酰丙氨酸-丙氨酸-脯氨酸-苯丙氨酸甲酯（25）与其相应的三氟甲基酮9a和9b进行比较，结果显示α-酮酯是更有效的抑制剂。同样，在猪胰弹性蛋白酶和人类中性粒细胞弹性蛋白酶检测中，乙酰基-脯氨酸-丙氨酸-脯氨酸-丙氨酸甲酯（21）比其相应的三氟甲基酮（9c）更有效。在一组丙氨酸-丙氨酸-脯氨酸-缬氨酸-三氟甲基弹性蛋白酶抑制剂中，苄氧羰基（Cbz）N保护基团作为弹性蛋白酶P5位点识别单元，比丹磺酰基、甲氧基琥珀酰基或叔丁氧羰基具有更高的效力。当从二甲基亚砜储备溶液中加入三氟甲基酮9f时，对弹性蛋白酶的初始抑制作用大于在检测前用缓冲液平衡时的抑制作用，这表明非水合酮是抑制剂更有效的形式。我们报道的最有效的弹性蛋白酶抑制剂是Nα-（金刚烷磺酰基）-Nε-（甲氧基琥珀酰基）-赖氨酸-脯氨酸-缬氨酸-三氟甲基（16），其抑制常数（Ki）为0.58 nM。
