Aromatase inhibitors. Syntheses and structure-activity studies of novel pyridyl-substituted indanones, indans, and tetralins

Article abstract of DOI:10.1021/jm00035a007

The (E)-2-(4-pyridylmethylene)-1-indanones (E)-1-(E)-5 [(E)-1, H; (E)-2, 4-OCH₃; (E)-3, 5-OCH₃; (E)-4, 4-OH; (E)-5, 5-OH] were obtained by aldol condensation of the corresponding 1-indanones with 4-pyridinecarboxaldehyde, and in case of the OH compound (E)-4 subsequent ether cleavage of (E)-2. The synthesis of the (Z)-isomers (Z)-1-(Z)-3 [(Z)-1, H; (Z)-2, 4-OCH₃; (Z)-3, 5- OCH₃] was accomplished by UV irradiation of the corresponding (E)-isomers. Catalytic hydrogenation of (E)-1-(E)-3 gave the 2-(4-pyridylmethyl)-1- indanones 6-8 (6, H; 7, 4-OCH₃; 8, 5-OCH₃). The 2-(4-pyridylmethyl)- substituted indans 11-13 (11, H; 12, 4-OCH₃; 13, 5-OCH₃) and the tetralins 16-19 (16, H; 17, 5-OCH₃; 18, 6-OCH₃; 19, 7-OCH₃) were obtained by reduction of the corresponding ketones using N₂H₄/KOH. The 2-(4- pyridylmethyl)-substituted indanones 9 (4-OH) and 10 (5-OH), indans 14 (4- OH) and 15 (5-OH), and tetralins 20-22 (20, 5-OH; 21, 6-OH; 22, 7-OH) were synthesized by ether cleavage of the corresponding OCH₃ compounds. All compounds showed inhibition of human placental aromatase exhibiting relative potencies from 0.9 [(E)-4] to 163 [18; aminoglutethimide (AG) potency χ 1]. Compounds 13 and 18 showed competitive type of inhibition and a type II difference spectrum, indicating the interaction of the pyridyl-N with the central Fe(III) ion of the cytochrome P450 heme component. Only the OH- substituted indans and tetralins inhibited bovine adrenal desmolase with maximum activity shown by 20 and 22 (12% inhibition, 25 μM; AG, 53% inhibition, 25 μM). In vivo, however, all tested aromatase inhibitors (6, 8, 10, 14, 15, 18 and 20) were less active than AG concerning the inhibition of the uterotrophic activity of androstenedione (6, 8, 10, 15), the reduction of the plasma estradiol concentration (14, 20), and the mammary carcinoma (MC) inhibiting properties (18, 20; androstenedione-stimulated juvenile rats, pregnant mares' serum gonadotropin-primed rats as well as dimethylbenzanthracene-induced MC of the Sprague-Dawley rat, postmenopausal experiment). Since no affinity to the estrogen receptor was demonstrated (20), estrogenic effects as a cause for the poor tumor inhibiting activity have to be excluded.