A novel series of thromboxane A2 synthetase inhibitors with free radical scavenging and anti-peroxidative activities |
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Authors: | Kamiya S Shirahase H Nakamura S Kanda M Matsui H Yoshimi A Kasai M Takahashi K Kurahashi K |
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Institution: | Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan. |
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Abstract: | 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. |
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