1-Alkyl analogues of aminoglutethimide. Comparative inhibition of cholesterol side chain cleavage and aromatase and metabolism of the 1-propyl derivative, a highly selective inhibitor of aromatase.
A homologous series of 1-n-alkyl-derivatives of aminoglutethimide (AG) has been synthesised and tested for inhibitory activity towards the cholesterol side chain cleavage enzyme (desmolase) from bovine adrenals and human placental aromatase in an attempt to find a selective aromatase inhibitor. Activity against desmolase declined from an IC50 value of 30 microM for the parent drug to 220 microM for the n-propyl derivative but increased again thereafter. Against aromatase, activity was least for the methyl and ethyl derivatives and highest (IC50 = 1.6 microM) for the hexyl and octyl analogues. The optimal ratio IC50 (desmolase):IC50 aromatase of 44 was found for the n-propyl derivative, which was therefore selected for preliminary metabolism studies using rat and mouse liver microsomes and hepatocytes and in these species in vivo. There were parallels with AG, most notably in the analogous formation from the n-propyl derivative of an arylhydroxylamine in the mouse.
Seago
A
A
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Baker
M H
MH
Houghton
J
J
Jarman
M
M
Leung
C S
CS
Rowlands
M G
MG
D000107:Acetylation; D000616:Aminoglutethimide / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D047072:Aromatase Inhibitors; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D000616:Aminoglutethimide; D002786:Cholesterol Side-Chain Cleavage Enzyme