title: Development of dual-acting benzofurans for thromboxane A2 receptor antagonist and prostacyclin receptor agonist: synthesis, structure-activity relationship, and evaluation of benzofuran derivatives.
abstract: Prostacyclin (PGI(2)) is an unstable, powerful endogenous inhibitor of platelet aggregation, and thromboxane A(2) (TXA(2)) is an unstable endogenous arachidonic acid metabolite that plays a pivotal role in platelet aggregation and vasoconstriction. The balance between TXA(2) and PGI(2) greatly affects maintenance of the homeostasis of the circulatory system. A novel series of benzofuran-7-yloxyacetic acid derivatives was discovered as potent dual-acting agents to block the thromboxane A(2) receptor and to activate the prostacyclin receptor. Synthesis, structure-activity relationship, and in vitro and ex vivo pharmacology of this series of compounds are described. The most potent in the series was {3-[2-(1,1-diphenylethylsulfanyl)ethyl]-2-hydroxymethylbenzofuran-7-yloxy}acetic acid diethanolamine salt (7) with K(i) of 4.5 nM for thromboxane receptor antagonism and K(i) of 530 nM for prostacyclin receptor agonism. Remarkably, compound 7 is a promising candidate for novel treatment as an antithrombotic agent with other cardiovascular actions to avoid hypotensive side effects.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries Inc., 1,111 Tebiro, Kamakura, Kanagawa 248-8555, Japan. michihiro_ono@nts.toray.co.jp
authors.forename: Michihiro
authors.initials: M
authors.lastname: Ohno
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hoshi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtake
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011869:Radioligand Assay; D044006:Receptors, Epoprostenol / Q000819:agonists*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C503901:(3-(2-(1,1-diphenylethylsulfanyl)ethyl)-2-hydroxymethylbenzofuran-7-yloxy)acetic acid; D001572:Benzofurans; D005343:Fibrinolytic Agents; D044006:Receptors, Epoprostenol; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013440:Sulfides