title: Esters of 3-pyridylacetic acid that combine potent inhibition of 17 alpha-hydroxylase/C17,20-lyase (cytochrome P45017 alpha) with resistance to esterase hydrolysis.
abstract: Esters of 3- and 4-pyridylacetic acid have been prepared and tested for inhibitory activity toward the human testicular 17 alpha-hydroxylase/C17,20-lyase and human placental aromatase enzymes. The structural features required for optimal inhibition of the hydroxylase/lyase enzyme were a 3-pyridine ring, methyl substitution alpha to the carbonyl group, and a bulky alkoxycarbonyl substituent. The compounds with the greatest selectivity were isopinocampheyl 2-methyl-2-(3-pyridyl)propanoate, 9, 1-adamantyl 2-methyl-2-(3-pyridyl)propanoate, 12, and 2-methyl-2-adamantyl 2-methyl-2-(3-pyridyl)propanoate, 14, which, while inhibiting the aromatase activity with IC50 values of 30, 35, and 40 microM, respectively, exhibited IC50 values toward hydroxylase/lyase of between 13 and 90 nM. For comparison, ketoconazole gave an IC50 value of 15 microM against aromatase and values of 65 and 26 nM for inhibition of the hydroxylase and lyase activities, respectively. Some of the structural features required for enzyme inhibition also conferred resistance to esterase hydrolysis, in vitro using rat liver microsomes as a source of the esterase activity. Therefore these esters are lead compounds in the development of inhibitors of androgen biosynthesis for the treatment of hormone-dependent prostatic cancer.
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism*; D004952:Esters; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010920:Placenta / Q000201:enzymology; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013737:Testis / Q000201:enzymology
chemical_list: C096243:1-adamantyl 2-methyl-2-(3-pyridyl)propanoate; C096244:2-methyl-2-adamantyl 2-methyl-2-(3-pyridyl)propanoate; D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D004952:Esters; D011422:Propionates; C096242:isopinocampheyl 2-methyl-2-(3-pyridyl)propanoate; D013254:Steroid 17-alpha-Hydroxylase; D004950:Esterases; D000218:Adamantane