Novel Irreversible Aromatase Inhibitors

Abstract

The aromatization of C19 steroids to obtain CIS estrogens (FIG. 1) constitutes the last and one of the most important steps in the biosynthetic progression from cholesterol to estrogens.The aromatase system is an enzyme complex consisting of two components, a flavoprotein NADPH-cytochrome P-450 reductase that transfers electrons from NADPH to the terminal enzyme and a specific form of cytochrome P-450 known as aromatase cytochrome P-450.The latter protein is involved in the binding of Clg-steroid substrates and catalyzes the multistep reaction leading to aromatization of the A ring of the steroid.' Specific inhibitors of this enzyme complex may be useful in controlling pathologic conditions associated with estrogens, such as breast cancer, endometrial cancer, and benign prostatic h y p e r p l a ~i a .~. ~ Compounds that interfere with the aromatase enzyme complex may be classified as reversible inhibitors or irreversible, mechanism-based, aromatase inhibitors (TABLE I).Reversible aromatase inhibitors are competitive inhibitors of cytochrome P-450, and aminoglutethimide (AG) may be regarded as the pioneer drug of this type.AG (OrimetenD) was initially introduced as an anticonvulsant and its endocrine properties became apparent only after extensive clinical use.eAlthough the drug has been of some benefit in postmenopausal breast cancer, it is a nonspecific aromatase inhibitor and presents some problems with tolerability.Several nonsteroidal reversible aromatase inhibitors, more selective than AG, have recently been described.Among them, the analogs resembling AG itself are the pyridyl derivative (pyridoglutethimide) described by Foster et al. ' and the 3and 4-alkylated derivatives, such as 3-(4'-aminophenyl)-3-isopentyl-piperidine-2,6-dione, described by Hartman et ~1 .~ Several imidazole antimycotic agents and analogs have been described as aromatase inhibitors, although some of them appear unsele~tive.~More recently two selective and potent reversible aromatase inhibitors have been described, LY 1 13 174 (8-chloro-5-(4-chlorophenyl)-5H-indeno( 1 ,2D)pyrimidine)Io and CGS 16949A (4-(5,6,7,8-tetra-hydrimidazo[l,5-a]pyridin-5-yl)-benzonitrile