Inhibition of enzymes of estrogen and androgen biosynthesis by esters of 4-pyridylacetic acid.
A variety of esters of 4-pyridylacetic acid have been prepared by base mediated exchange from the methyl ester. Several of the esters of alcohols that contained a cyclohexyl ring were potent inhibitors of human placental aromatase and of the rat testicular 17 alpha-hydroxylase/C17-20lyase complex. The most potent agents found against both enzyme complexes were the borneyl, isopinocampheyl, and 1-adamantyl esters. These were over 100 times more potent than aminoglutethimide against aromatase and of greater potency than ketoconazole against hydroxylase/lyase. Potency against either enzyme complex was reduced if the ester function was borne on the cyclohexyl ring in an axial rather than an equatorial position. Some differential selectivity could be introduced since whereas methyl substitution adjacent to the carbonyl group reduced the inhibition of aromatase, it increased that against hydroxylase/lyase.
McCague
R
R
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, England.
Rowlands
M G
MG
Barrie
S E
SE
Houghton
J
J
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D047072:Aromatase Inhibitors; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004952:Esters; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology
D000085:Acetates; D000728:Androgens; D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004952:Esters; D004967:Estrogens; D011725:Pyridines; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D000446:Aldehyde-Lyases