Enzyme-activated inhibitors of steroidal hydroxylases.
Cytochrome P450 monooxygenases (CYP450) of the steroid biosynthetic pathways are highly substrate specific in comparison to the variable specificities of hepatic CYP450 enzymes. Both groups of enzymes catalyze the reductive cleavage of molecular oxygen with transfer of oxygen to the substrate to form hydroxylated derivatives. Those steroids formed in endocrine tissues represent highly specific endocrine/autocrine hormones with enhanced biological potency, while hepatic hydroxylation of steroids reduces their endocrine bioactivities and enhances urinary elimination. Changes of the hormonal milieu of endocrine and peripheral tissues are associated with the development of hyperplastic and/or malignant conditions. Hormone deprivation induces regression of endocrine dependent growth via apoptosis and may also alter growth of hormone insensitive cells by the induction of negative growth factors. Biosynthetic CYP450 enzymes of those steroids that mediate specific disease processes are potential therapeutic targets for selective intervention. This objective can be accomplished by the design of specific pseudo-substrate analogs that will be activated during enzyme-directed catalysis to produce a reactive functional group in the enzyme's active site that will either tightly or irreversibly bind and inactivate the host enzyme. The CYP450 enzymes that hydroxylate the C19 carbon of androgens (aromatase) and the C18 carbon of corticosterone (aldosterone synthase) were selected as target enzymes because they are terminal enzymes of biosynthetic pathways which hydroxylate specific angular methyl groups. Hypersecretion of their respective hormonal products, estrogens and aldosterone, are associated with specific disease conditions. Substrate analogs containing ethynyl, vinyl, or nitrile groups attached to the C19 or C18 methyl groups were enzyme-activated inhibitors. The ethynyl analogs, 19-acetylenic androstenedione (Plomestane) and 18-acetylenic deoxycorticosterone, had nanomolar inhibitory constants (Ki values) and were irreversible inactivators of their target enzymes in animal models.
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
J O
JO
Johnston
C L
CL
Wright
G W
GW
Holbert
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D019405:Cytochrome P-450 CYP11B2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004361:Drug Tolerance; D004967:Estrogens / Q000097:blood; D006801:Humans; D008297:Male; D008901:Mineralocorticoids / Q000378:metabolism / Q000494:pharmacology; D010293:Pargyline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000378:metabolism; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D015384:Zona Glomerulosa / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004967:Estrogens; D008901:Mineralocorticoids; D011987:Receptors, Steroid; D000735:Androstenedione; D003900:Desoxycorticosterone; C071418:18-ethynyldeoxycorticosterone; D010293:Pargyline; D013250:Steroid Hydroxylases; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; C033071:plomestane