Enzyme Inhibition Studies with Derivatives of Aminoglutethimide

Abstract

Aminoglutethimide, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione, (AG) in combination with replacement glucocorticoid is an effective endocrine therapy in advanced postmenopausal breast cancer (Santen, Breast Cancer Res. and Treat. 1: 183, 1981). AG blocks oestrogen biosynthesis via inhibition of peripheral aromatase and adrenal desmolase enzyme complexes. The aromatase blockage appears to be the clinically relevant site of action and the development of a potent, specific aromatase inhibitor would be of therapeutic advantage. 3-(4-aminophenyl)-1-ethylpyrrolodine-2,5-dione (I) and its N- methylated analogue (II) have been synthesised and assayed in vitro for activity against bovine adrenal desmolase and human placental aromatase. Comparison was made with AG and its N-methylated analogue (III). Compound I was as potent as AG against aromatase, with little activity against desmolase indicating that for these 4-aminophenyl derivatives the pyrrolidinedione ring confers greater selectivity of action than the piperidinedione ring system of AG. The methylated analogues displayed weak, non-selective inhibition. Analogues of AG and compound I lacking the amino group or substituted with a nitro group were weakly active against both enzymes, indicating the importance of the amino moiety for inhibitory activity. Further analogues of AG and compound I are being synthesised to explore the structure activity relationships.