Synthesis of 2(1H)-quinolinone derivatives and their inhibitory activity on the release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) from platelets.
A search for potent inhibitors of release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE), which plays an important role in the pathogenesis of various circulatory disorders and arteriosclerosis, led us to 6-[4-(1-cyclohexyl-5-tetrazolyl)butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) and 2(1H)-quinolinone derivatives having an azole group in the side chain. Many 2(1H)-quinolinone derivatives were synthesized and tested in vitro for the inhibitory activity in human platelets. 3,4-Dihydro-6-[3-(1-o-tolylimidazol-2-yl)sulfinylpropoxy]-2( 1H)-quinolinone (5k) was found to be one of the most potent inhibitors of 12-HETE release, being more potent than esculetin. In addition, the sulfoxide 5k showed in vivo inhibitory activity on platelet adhesion in rats. Since 5k is racemic, the enantiomers were prepared and their potencies were compared in vitro and in vivo. (S)-(+)-5k had the best pharmacological profile and was selected as a candidate drug for further development. The structure-activity relationships are discussed.
Third Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
T
T
Uno
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Y
Ozeki
Y
Y
Koga
G N
GN
Chu
M
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Okada
K
K
Tamura
T
T
Igawa
F
F
Unemi
M
M
Kido
T
T
Nishi
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D006893:Hydroxyeicosatetraenoic Acids; D015363:Quinolones; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid