Isosorbide-based aspirin prodrugs: integration of nitric oxide releasing groups.
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.
Jones
Michael
M
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
Inkielewicz
Iwona
I
Medina
Carlos
C
Santos-Martinez
Maria Jose
MJ
Radomski
Anna
A
Radomski
Marek W
MW
Lally
Maeve N
MN
Moriarty
Louise M
LM
Gaynor
Joanne
J
Carolan
Ciaran G
CG
Khan
Denise
D
O'Byrne
Paul
P
Harmon
Shona
S
Holland
Valerie
V
Clancy
John M
JM
Gilmer
John F
JF
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
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