iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
J Med Chem. 2010 Jan 14;53(1):241-53. doi: 10.1021/jm901082k.
Human leukocyte elastase (HLE) is a serine protease stored in and secreted from neutrophils that plays a determinant role in the pathogenesis of several lung diseases. 4-Oxo-beta-lactams, previously reported as acylating agents of porcine pancreatic elastase, were found to be selective and potent inhibitors of HLE. Structure-activity relationship analysis showed that inhibitory activity is very sensitive to the nature of C-3 substituents, with small alkyl substituents such as a gem-diethyl group improving the inhibitory potency when compared to gem-methyl benzyl or ethyl benzyl counterparts. 4-Oxo-beta-lactams containing a heteroarylthiomethyl group on the para position of an N(1)-aryl moiety afforded highly potent and selective inhibition of HLE, even at a very low inhibitor to enzyme ratio, as shown by the k(on) value of 3.24 x 10(6) M(-1) s(-1) for 6f. The corresponding ortho isomers were 40- to 90-fold less potent.
人白细胞弹性蛋白酶（HLE）是一种丝氨酸蛋白酶，储存在中性粒细胞中并从其中分泌出来，在几种肺部疾病的发病机制中起决定性作用。4-氧代-β-内酰胺先前被报道为猪胰弹性蛋白酶的酰化剂，被发现是 HLE 的选择性和有效抑制剂。结构-活性关系分析表明，抑制活性对 C-3 取代基的性质非常敏感，与 gem-甲基苄基或乙基苄基相比，小烷基取代基如 gem-二乙基基团可提高抑制效力。在 N（1）-芳基部分的对位上含有杂芳基硫甲基的 4-氧代-β-内酰胺对 HLE 具有高度有效和选择性的抑制作用，即使在抑制剂与酶的比例非常低的情况下也是如此，如 6f 的 k(on)值为 3.24 x 10(6) M(-1) s(-1) 所示。相应的邻位异构体的效力低 40-90 倍。
