Thromboxane A2 synthetase inhibitors. 2. Syntheses and activities of tetrahydronaphthalene and indan derivatives.
A series of 1-imidazolylalkyl-substituted or 5-thiazolylalkyl-substituted tetrahydronaphthalenecarboxylic acid and indancarboxylic acid derivatives were prepared and tested for the inhibitory activities of thromboxane A2 (TXA2) production in vitro and ex vivo. Most of the compounds showed potent TXA2 synthetase inhibitory activities in vitro and had long duration of inhibition of TXA2 production in rats when orally or intravenously administrated. The imidazole analogues had slightly less potency in vitro than the thiazole analogues, but the activities of the imidazole analogues in ex vivo models were equal or superior to the activities of the thiazole analogues. 6-(1-Imidazolyl-methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride hemihydrate (47a, DP-1904) was chosen for clinical studies.
Kanao
M
M
Research Institute, Daiichi Seiyaku Co., Ltd., Tokyo, Japan.
Watanabe
Y
Y
Kimura
Y
Y
Saegusa
J
J
Yamamoto
K
K
Kanno
H
H
Kanaya
N
N
Kubo
H
H
Ashida
S
S
Ishikawa
F
F
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D055598:Chemical Phenomena; D002621:Chemistry; D015232:Dinoprostone / Q000097:blood; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D015394:Molecular Structure; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000097:blood
D007189:Indans; D007192:Indenes; D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D013930:Thromboxane-A Synthase; D015232:Dinoprostone