title: Isosorbide-based aspirin prodrugs: integration of nitric oxide releasing groups.
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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Jones
authors.forename: Iwona
authors.initials: I
authors.lastname: Inkielewicz
authors.forename: Carlos
authors.initials: C
authors.lastname: Medina
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Santos-Martinez
authors.forename: Anna
authors.initials: A
authors.lastname: Radomski
authors.forename: Marek W
authors.initials: MW
authors.lastname: Radomski
authors.forename: Maeve N
authors.initials: MN
authors.lastname: Lally
authors.forename: Louise M
authors.initials: LM
authors.lastname: Moriarty
authors.forename: Joanne
authors.initials: J
authors.lastname: Gaynor
authors.forename: Ciaran G
authors.initials: CG
authors.lastname: Carolan
authors.forename: Denise
authors.initials: D
authors.lastname: Khan
authors.forename: Paul
authors.initials: P
authors.lastname: O'Byrne
authors.forename: Shona
authors.initials: S
authors.lastname: Harmon
authors.forename: Valerie
authors.initials: V
authors.lastname: Holland
authors.forename: John M
authors.initials: JM
authors.lastname: Clancy
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D001241:Aspirin / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000097:blood; D004952:Esters; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007547:Isosorbide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D009566:Nitrates / Q000138:chemical synthesis* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004952:Esters; D009566:Nitrates; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; C545533:isosorbide-2-aspirinate-5-(2-nitroxymethyl)benzoate; C545534:isosorbide-2-aspirinate-5-(3-nitrooxymethyl)benzoate; D002091:Butyrylcholinesterase; D001241:Aspirin; D007547:Isosorbide