Development of 3,4-dihydro-2H-benzo[1,4]oxazine derivatives as dual thromboxane A2 receptor antagonists and prostacyclin receptor agonists.
We discovered a novel series of 3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxyacetic acid derivatives as potent dual-acting agents to block the TXA2 receptor and to activate the PGI2 receptor. We report the synthesis, structure-activity relationship, and in vitro, ex vivo, and in vivo pharmacology of this series of compounds. 4-[2-(1,1-Diphenylethylsulfanyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxyacetic acid N-methyl-D-glucamine salt (7) is a promising candidate for a novel treatment in the anti-thrombotic and the cardiovascular fields avoiding 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
Tanaka
Yoichiro
Y
Miyamoto
Mitsuko
M
Takeda
Takahiro
T
Hoshi
Kazuhiro
K
Yamada
Naohiro
N
Ohtake
Atsushi
A
D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D044006:Receptors, Epoprostenol / Q000819:agonists*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D048588:Benzoxazines; D005343:Fibrinolytic Agents; D044006:Receptors, Epoprostenol; D044244:Receptors, Thromboxane A2, Prostaglandin H2