title: Design, synthesis and evaluation of aspirin analogues having an additional carboxylate substituent for antithrombotic activity.
abstract: Acetylsalicylic acid (aspirin) is an effective long-term prophylaxis of thrombotic events such as heart attacks and strokes. It covalently inhibits prostaglandin-H-synthase by interacting with Arg120 or Tyr385 at the active site allowing delivery of its acetyl group to Ser530. However the structure has not been optimized to fit the active site. We have designed acetylsalicylate analogues with an additional carboxylate substituent which allows simultaneous interaction with Arg120 and Tyr385 whilst positioning the acetyl group in close proximity to Ser530. One of these, an ester derivative which unlike acetylsalicylic acid is non-acidic, may act as useful lead compound for further exploitation of this approach.
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alagha
authors.forename: Edelmiro
authors.initials: E
authors.lastname: Moman
authors.forename: Mauro F A
authors.initials: MF
authors.lastname: Adamo
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Nolan
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chubb
mesh_terms: D001120:Arginine / Q000737:chemistry; D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004952:Esters; D006801:Humans; D015539:Platelet Activation; D010974:Platelet Aggregation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013927:Thrombosis / Q000188:drug therapy*; D014443:Tyrosine / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D004952:Esters; D014443:Tyrosine; D012694:Serine; D001120:Arginine; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin