title: New aromatase inhibitors. Synthesis and biological activity of pyridyl-substituted tetralone derivatives.
abstract: The (E)-2-(4-pyridylmethylene)-1-tetralones 1-7 (1, H; 2, 5-OCH3; 3, 6-OCH3; 4, 7-OCH3; 5, 5-OH; 6, 6-OH; 7, 7-OH) were obtained by aldol condensation of the corresponding 1-tetralones with 4-pyridinecarboxaldehyde, and in the case of the OH compounds 5 and 7 subsequent ether cleavage of the OCH3-substituted 2-(4-pyridylmethylene)-1-tetralones. Catalytic hydrogenation of 1-4 gave the 2-(4-pyridylmethyl)-1-tetralones 8-11 (8, H; 9, 5-OCH3; 10, 6-OCH3; 11, 7-OCH3). Subsequent ether cleavage of 9-11 led to the corresponding OH compounds 12-14 (12, 5-OH; 13, 6-OH; 14, 7-OH). The enantiomers of 11 and 12 were separated semipreparatively by HPLC on triacetylcellulose. All compounds (1-14) showed an inhibition of human placental aromatase exhibiting relative potencies from 2.2 to 213 [compounds 6 and (+)-12, respectively; aromatase inhibitory potency of aminoglutethimide (AG) = 1]. The compounds exhibited no or only a weak inhibition of desmolase [cholesterol side chain cleavage enzyme; maximum activity shown by 12, 23% inhibition (25 microM); AG, 53% inhibition (25 microM)]. In vivo, however, the compounds were not superior to AG as far as the reduction of the plasma estradiol concentration and the mammary carcinoma (MC) inhibiting properties are concerned (PMSG-primed SD rats as well as DMBA-induced MC of the SD rat, pre- and postmenopausal experiments, and the transplantable MXT-MC of the BD2F1 mouse). This is due to a fast decrease of the plasma E2 concentration inhibiting effect as could be shown by a kinetic experiment. In addition, select compounds inhibited rat ovarian aromatase much less than human placental aromatase (12, factor of 10). Estrogenic effects as a cause for the poor in vivo activity of the test compounds could be excluded, since they did not show affinity for the estrogen receptor.
authors.affiliation: Fachrichtung 12.1 Pharmazeutische Chemie, Universität des Saarlandes, Saarbrücken, F.R.G.
authors.forename: H
authors.initials: H
authors.lastname: Bayer
authors.forename: C
authors.initials: C
authors.lastname: Batzl
authors.forename: R W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: A
authors.initials: A
authors.lastname: Mannschreck
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D008190:Lyases / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D011725:Pyridines; D013764:Tetrahydronaphthalenes; D008190:Lyases