Synthesis of new potent and selective aromatase inhibitors based on long-chained diarylalkylimidazole and diarylalkyltriazole molecule skeletons.
A series of long-chained diarylalkylimidazoles and diarylalkyltriazoles were synthesized and evaluated for the inhibitory potency for aromatase (estrogen synthetase) activity in human placental microsomes. The relative specificity of inhibition was evaluated by measuring the inhibition of cholesterol side-chain cleavage enzyme (desmolase) in human placental mitochondria and the inhibition of 7-ethoxycoumarin O-deethylase (a typical drug-metabolizing enzyme activity) in rat liver microsomes. The structural requirements including substituent effects for the strongest potency and for the highest specificity were delineated. alpha,omega-Diarylalkyltriazoles and imidazoles were the most interesting molecules, in which the geometric and optical isomerism displayed remarkable selectivity for aromatase inhibition.
Department of Synthetic Chemistry, Orion Corporation, Orion Pharma, R&D, P.O. Box 65, Espoo, Finland. arto.karjalainen@orion.fi
A
A
Karjalainen
A
A
Kalapudas
M
M
Södervall
O
O
Pelkonen
R
R
Lammintausta
D000818:Animals; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D014230:Triazoles