ESTERS OF 3-PYRIDYLACETIC ACID THAT COMBINE POTENT INHIBITION OF 17-ALPHA-HYDROXYLASE C-17,C-20-LYASE (CYTOCHROME P45017-ALPHA) WITH RESISTANCE TO ESTERASE HYDROLYSIS

Esters of 3- and 4-pyridylacetic acid have been prepared and tested fo r inhibitory activity toward the human testicular 17 alpha-hydroxylase /C-17,C-20-lyase and human placental aromatase enzymes. The structural features required for optimal inhibition of the hydroxylase/lyase enz yme were a 3-pyridine ring, methyl substitution alpha to the carbonyl group, and a bulky alkoxycarbonyl substituent. The compounds with the greatest selectivity were isopinpcampheyl 2-methyl-2-(3-pyridyl)propan oate, 9, 1-adamantyl 2-methyl-2-(3-pyridyl)propanoate, 12, and 2-methy l-2-adamantyl 2-methyl-2-(3-pyridyl)propanoate, 14, which, while inhib iting the aromatase activity with IC50 values of 30, 35, and 40 mu M, respectively, exhibited IC50 values toward hydroxylase/lyase of betwee n 13 and 90 nM. For comparison, ketoconazole gave an IC50 value of 15 mu M against aromatase and values of 65 and 26 nM for inhibition of th e hydroxylase and lyase activities, respectively. Some of the structur al features required for enzyme inhibition also conferred resistance t o esterase hydrolysis, in vitro using rat liver microsomes as a source of the esterase activity. Therefore these esters are lead compounds i n the development of inhibitors of androgen biosynthesis for the treat ment of hormone-dependent prostatic cancer.