title: Evaluation of the racemate and the enantiomers of a new highly active and selective aromatase inhibitor of the aminoglutethimide type.
abstract: Compound 1 [3-(4-aminophenyl)-3-cyclohexylpiperidine-2,6-dione] is a highly potent nonsteroidal aromatase inhibitor of the aminoglutethimide (AG)-type containing an asymmetric carbon atom. 1 and its enantiomers (+)-1 and (-)-1 inhibited human placental aromatase by 50% at 0.3, 0.15, and 4.6 microM, respectively (IC50 AG = 37 microM). A competitive type of inhibition was observed for 1 and (+)-1 (Ki 1 = 3.9 nM, Ki (+)-1 = 2.0 nM, Ki AG = 408 nM). Using solubilized high spin aromatase, 1 showed a type II difference spectrum indicating the interaction of the amino nitrogen with the central Fe(III)-ion of the cytochrome P450 heme component. 1 and (+)-1 inhibited cholesterol side chain cleavage enzyme (desmolase) by 50% at 67 and 82 microM, respectively (IC50 AG = 29 microM). In ACTH-stimulated rat adrenal tissue in vitro, 1 was less active in inhibiting aldosterone and corticosterone production compared to AG (IC50s, 1, 130 and 140 microM, AG, 80 and 50 microM, respectively). In vivo, 1 was superior to AG, too: it showed a stronger inhibition of the plasma estradiol concentration of pregnant mares' serum gonadotropin-primed SD rats, the activity residing mainly in the (+)-enantiomer [ovarian vein: (+)-1, 0.31 mg/kg: 81% inhibition, (-)-1, 0.31 mg/kg: 6%, AG, 1.25 mg/kg: 35%]. Furthermore 1 was much more active in inhibiting the testosterone-stimulated tumor growth of the ovariectomized 9,10-dimethyl-1,2-benzanthracene tumor-bearing SD rat (postmenopausal model). Up to a dose of 600 mg/kg of 1 no central nervous symptom depressive effects were observed in the motility test and the rotarod experiment, whereas AG exhibited ED50s of 62 and 164 mg/kg, respectively.
authors: Fachrichtung 12.1 Pharmazeutische Chemie, Universität des Saarlandes, Saarbrücken, Germany.
authors: R W
authors: RW
authors: Hartmann
authors: G
authors: G
authors: Grün
authors: U
authors: U
authors: Bartz
authors: M
authors: M
authors: Palzer
mesh_terms: D000311:Adrenal Glands / Q000201:enzymology; D000450:Aldosterone / Q000096:biosynthesis; D000616:Aminoglutethimide / Q000494:pharmacology*; D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D003345:Corticosterone / Q000096:biosynthesis; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008190:Lyases / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D010881:Piperidones / Q000494:pharmacology*; D010920:Placenta / Q000201:enzymology; D051381:Rats; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: D047072:Aromatase Inhibitors; D010881:Piperidones; D000616:Aminoglutethimide; C075253:3-(4-aminophenyl)-3-cyclohexylpiperidine-2,6-dione; D000450:Aldosterone; D004958:Estradiol; D008190:Lyases; D003345:Corticosterone