A new class of potent, selective, nonsteroidal inhibitors of aromatase have been discovered. The most potent member of this series is fadrozole hydrochloride, CGS 16949 A, 4-(5,6,7,8-tetrahydroimidazo[1,5-alpha]pyridin-5-yl)benzonitrile monohydrochloride, 26a. In addition, the 6,7-dihydropyrrolo[1,2-c]imidazole (21a) and the 6,7,8,9-tetrahydroimidazo[1,5-alpha]azepine (21b) analogues were synthesized and evaluated. CGS 16949 A's ability to selectively inhibit aromatase (IC50 = 4.5 nM) over other cytochrome P-450 enzymes and suppress estrogen production when administered orally make it a suitable candidate to test the potential of an aromatase inhibitor in estrogen-dependent diseases including breast cancer.
The synthesis and structure-activity profile of a new class of potent and highly specific thromboxane A2 synthetase inhibitors is described. The most potent member of this series in vitro is determined to be imidazo[1,5-a]-pyridine-5-hexanoic acid (9).
The preparation of a series of 1-glutarylindoline-2(S)-carboxylic acid derivatives, 6a-v and 21a-c, is described. The above compounds were tested for inhibition of angiotensin converting enzyme. The structure-activity relationship of the series is also discussed. Compound 6u, the most potent member of the series, had an in vitro IC50 of 4.8 X 10(-9) M. Compound 6v, an ethyl ester of 6u, lowered blood pressure 70 mm in spontaneous hypertensive rats at an oral dose of 30 mg/kg.
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