2. Academic Validation
  3. Isosorbide-based aspirin prodrugs: integration of nitric oxide releasing groups

Isosorbide-based aspirin prodrugs: integration of nitric oxide releasing groups

  • J Med Chem. 2009 Nov 12;52(21):6588-98. doi: 10.1021/jm900561s.
Michael Jones 1,  Iwona Inkielewicz,  Carlos Medina,  Maria Jose Santos-Martinez,  Anna Radomski,  Marek W Radomski,  Maeve N Lally,  Louise M Moriarty,  Joanne Gaynor,  Ciaran G Carolan,  Denise Khan,  Paul O'Byrne,  Shona Harmon,  Valerie Holland,  John M Clancy,  John F Gilmer
Affiliations

Affiliation

  • 1 School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
PMID: 19821574 DOI: 10.1021/jm900561s
Abstract

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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z