A novel series of thromboxane A2 synthetase inhibitors with free radical scavenging and anti-peroxidative activities.
A novel series of indoline derivatives with imidazole and carboxyl moieties were synthesized and evaluated for their thromboxane A2 (TXA2) synthetase inhibiting, radical scavenging and anti-peroxidative activities. Among the compounds synthesized, 3-[5-substituted-3-[2-(imidazol-1-yl)ethyl]indolin-1-yl]propionic acids showed free radical scavenging activity and inhibitory effects on lipid-peroxidation of rat brain homogenate and on arachidonate-induced TXA2-dependent aggregation of rabbit platelets. The anti-platelet and anti-peroxidative activities were related to the lipophilicity of the 5-substituent. The 5-hexyloxy derivative (13) showed about 35-fold higher inhibitory activity on TXA2 synthesis than that of ozagrel and about 100-fold higher activity on lipid peroxidation than that of alpha-tocopherol. Compound 13 showed in vivo anti-thrombotic effect in mice and ex vivo anti-peroxidative activity in rats.
Kamiya
S
S
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
Shirahase
H
H
Nakamura
S
S
Kanda
M
M
Matsui
H
H
Yoshimi
A
A
Kasai
M
M
Takahashi
K
K
Kurahashi
K
K
D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D015764:Bepridil / Q000031:analogs & derivatives* / Q000737:chemistry; D001713:Biphenyl Compounds; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000201:enzymology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D015227:Lipid Peroxidation / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D010851:Picrates; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007202:Indicators and Reagents; D010851:Picrates; D016718:Arachidonic Acid; D015764:Bepridil; C004931:1,1-diphenyl-2-picrylhydrazyl; D013930:Thromboxane-A Synthase