Sykes Nicholas O, Macdonald Simon J F, Page Michael I
Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield, HD1 3DH, U.K.
J Med Chem. 2002 Jun 20;45(13):2850-6. doi: 10.1021/jm0111245.
A series of bicyclic trans-fused gamma-lactones and gamma-lactams have been previously described for the inhibition of human neutrophil elastase and as possible development candidates. During the discovery program, it had been assumed that their acylating power was due in part to the inherent strain energy in the bicyclic structure that was released upon ring opening. This is now shown not to be the case, and in fact, these compounds are no more reactive than simple but analogous gamma-lactams and gamma-lactones. The strain energy is not released in the transition state for alkaline hydrolysis or alcoholysis because the reaction proceeds with rate-limiting formation of the tetrahedral intermediate. A reactivity index of k(OH) is proposed as a simple guide to determine the usefulness of a potential inhibitor as an enzyme acylating agent.
先前已描述了一系列双环反式稠合的γ-内酯和γ-内酰胺，它们可抑制人中性粒细胞弹性蛋白酶，并且有可能成为候选开发药物。在发现计划期间，人们曾认为它们的酰化能力部分归因于双环结构中固有的应变能，该应变能在开环时释放。现在表明情况并非如此，实际上，这些化合物并不比简单的类似γ-内酰胺和γ-内酯更具反应性。在碱性水解或醇解的过渡态中，应变能不会释放，因为反应以四面体中间体的限速形成进行。提出了k(OH)反应性指数作为一个简单的指南，以确定潜在抑制剂作为酶酰化剂的有效性。
