Development of dual-acting benzofurans for thromboxane A2 receptor antagonist and prostacyclin receptor agonist: synthesis, structure-activity relationship, and evaluation of benzofuran derivatives.
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.
Ohno
Michihiro
M
Pharmaceutical Research Laboratories, Toray Industries Inc., 1,111 Tebiro, Kamakura, Kanagawa 248-8555, Japan. michihiro_ono@nts.toray.co.jp
Miyamoto
Mitsuko
M
Hoshi
Kazuhiro
K
Takeda
Takahiro
T
Yamada
Naohiro
N
Ohtake
Atsushi
A
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
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