title: ASP6537, a novel highly selective cyclooxygenase-1 inhibitor, exerts potent antithrombotic effect without "aspirin dilemma".
abstract: BACKGROUND
  Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect.
  
  
  METHODS
  We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs.
  
  
  RESULTS
  The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were >142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥100 mg/kg.
  
  
  CONCLUSIONS
  ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect.
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. chinatsu.sakata@astellas.com
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Sakata
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kato
authors.forename: Masaki
authors.initials: M
authors.lastname: Abe
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohmiya
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Funatsu
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Morita
authors.forename: Masamichi
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011464:Epoprostenol / Q000378:metabolism / Q000652:urine; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D011453:Prostaglandins / Q000097:blood / Q000378:metabolism; D051381:Rats; D013270:Stomach / Q000187:drug effects; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014456:Ulcer / Q000139:chemically induced
chemical_list: C561773:3-methoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole; D016861:Cyclooxygenase Inhibitors; D005343:Fibrinolytic Agents; D011453:Prostaglandins; D014230:Triazoles; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D001241:Aspirin
keywords: AA; ACS; Arachidonic acid; Aspirin; COX; Cyclooxygenase; DMSO; GI; MC; MED; MI; NSAIDs; PGI(2); PRP; Platelet; Prostaglandin I(2); TTO; TXA(2); Thrombosis; Thromboxane A(2); acute coronary syndrome; cyclooxygenase; dimethylsulfoxide; gastrointestinal; methylcellulose; minimum effective dose; myocardial infarction; non-steroidal anti-inflammatory drugs; platelet-rich plasma; prostaglandin I(2); thromboxane A(2); time to occlusion