PMID: 3755630Jan 1, 1986Paper

Pharmacology of aminoglutethimide: structure/activity relationships and receptor interactions

Breast Cancer Research and Treatment
P J NichollsH J Smith

Abstract

The structure/activity relationships for inhibition of aromatase and cholesterol side-chain cleavage enzyme (CSCC) by aminoglutethimide and some of its analogues are reviewed. Although more effective against aromatase than CSCC, aminoglutethimide markedly inhibits both enzymes. Optimal competitive antagonism of aromatase is obtained with a free amino or basic group at the 4' position of the phenyl ring substituent. This is important because two major metabolites of aminoglutethimide where the amino group is conjugated have low or no inhibitory effect on aromatase. Relocation of the free amino group to the nitrogen atom of the piperidinedione ring enhances CSCC inhibition. The piperidinedione ring is not essential for inhibitory activity, several 4'-aminophenyl pyrrolidinediones being as potent as aminoglutethimide for aromatase but less effective against CSCC. In this series 3-(4'-aminophenyl)-pyrrolidine-2,5-dione is a selective aromatase inhibitor. Inactivity of 4'-aminophenyl derivatives of imidazolidinedione and pyrimidinetrione indicate that the 4'-aminophenyl moiety alone is insufficient for antagonist activity against aromatase. Replacement of the aminophenyl group by the stronger basic 4-pyridyl moiety in aminoglutethim...Continue Reading

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