3-(1-imidazolylmethyl) indoles: potent and selective inhibitors of human blood platelet thromboxane synthetase.
Several 3-(1-imidazolylmethyl) indoles were tested for inhibition of the microsomal enzymes which catalyse the biosynthesis of thromboxane A2, prostaglandin I2, and prostaglandin endoperoxides. These products were measured by bioassay to assess levels of enzyme activity. The highest activity against human blood platelet thromboxane A2-synthetase was obtained with 2-cyclopropyl-3(1-imidazolylmethyl) indole (IC50 1 x 10(-10) M). This compound also exhibited the highest activity against pig aorta prostaglandin I2-synthetase (IC50 8.4 x 10(-7) M). Of much more potential therapeutic interest, 2-isopropyl-3-(1-imidazolylmethyl) indole showed almost complete selectivity against thromboxane A2-synthetase. Both compounds exhibited IC50's of 2 x 10(-8) M against the latter enzyme but showed only weak effects (IC50's greater than 10(-4) M) against prostaglandin I2-synthetase and ram seminal vesicle PGH2-synthetase.
D000818:Animals; D001011:Aorta / Q000201:enzymology; D001792:Blood Platelets / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep; D013552:Swine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000097:blood
D007211:Indoles; D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D010088:Oxidoreductases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase; C002092:nictindole; D008797:Metyrapone