Jones Michael, Inkielewicz Iwona, Medina Carlos, Santos-Martinez Maria Jose, Radomski Anna, Radomski Marek W, Lally Maeve N, Moriarty Louise M, Gaynor Joanne, Carolan Ciaran G, Khan Denise, O'Byrne Paul, Harmon Shona, Holland Valerie, Clancy John M, Gilmer John F
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
J Med Chem. 2009 Nov 12;52(21):6588-98. doi: 10.1021/jm900561s.
Aspirin prodrugs and related nitric oxide releasing compounds hold significant therapeutic promise, but they are hard to design because aspirin esterification renders its acetate group very susceptible to plasma esterase mediated hydrolysis. Isosorbide-2-aspirinate-5-salicylate is a true aspirin prodrug in human blood because it can be effectively hydrolyzed to aspirin upon interaction with plasma BuChE. We show that the identity of the remote 5-ester dictates whether aspirin is among the products of plasma-mediated hydrolysis. By observing the requirements for aspirin release from an initial panel of isosorbide-based esters, we were able to introduce nitroxymethyl groups at the 5-position while maintaining ability to release aspirin. Several of these compounds are potent inhibitors of platelet aggregation. The design of these compounds will allow better exploration of cross-talk between COX inhibition and nitric oxide release and potentially lead to the development of selective COX-1 acetylating drugs without gastric toxicity.
阿司匹林前药及相关的一氧化氮释放化合物具有显著的治疗前景，但由于阿司匹林酯化使其乙酰基极易受到血浆酯酶介导的水解作用，因此很难设计。异山梨醇-2-阿司匹林酯-5-水杨酸盐在人体血液中是一种真正的阿司匹林前药，因为它与血浆丁酰胆碱酯酶相互作用时可有效水解为阿司匹林。我们发现，远端5-酯的结构决定了阿司匹林是否为血浆介导水解的产物之一。通过观察从一组基于异山梨醇的酯类中释放阿司匹林的条件，我们能够在5-位引入硝氧甲基，同时保持释放阿司匹林的能力。其中几种化合物是血小板聚集的强效抑制剂。这些化合物的设计将有助于更好地探索环氧化酶（COX）抑制与一氧化氮释放之间的相互作用，并有可能开发出无胃毒性的选择性COX-1乙酰化药物。
