Mulchande Jalmira, Guedes Rita C, Tsang Wing-Yin, Page Michael I, Moreira Rui, Iley Jim
iMed UL, CECF, Faculdade de Farmácia, Universidade de Lisboa, Av. Forças Armadas, Lisbon, Portugal.
J Med Chem. 2008 Mar 27;51(6):1783-90. doi: 10.1021/jm701257h. Epub 2008 Feb 22.
A new class of inhibitors 4-oxo-beta-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-beta-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl- N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett rho-value of 0.65. Compared with a rho-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of approximately 5 x 10 (5) M (-1) s (-1).
一类新型抑制剂4-氧代-β-内酰胺（氮杂环丁烷-2,4-二酮），含有分子识别所需的结构元件，可抑制猪胰弹性蛋白酶（PPE），但与类似的抑制剂3-氧代-β-磺内酰胺相比，对氢氧化物的反应性显著降低。抑制作用是活性位点丝氨酸酰化以及3,3-二乙基-N-芳基衍生物中N-（4-芳基）位置的吸电子取代基增加酶酰化速率并产生哈米特ρ值为0.65的结果。与同一系列碱性水解速率的ρ值0.96相比，这表明酶催化反应的过渡态更早。对接研究表明抑制剂与酶存在有利的非共价相互作用。化合物2i是对PPE最有效的抑制剂，也是一种非常有效的人白细胞弹性蛋白酶（HLE）抑制剂，酶失活的二级速率约为5×10⁵ M⁻¹ s⁻¹。
