Novel P450(17alpha) inhibitors: 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androstene derivatives.

Twelve 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androsta-5,16-diene derivatives were designed and synthesized from 3 beta-acetoxy-pregna-5,16-dien-20-one (1b) as inhibitors of 17 alpha-hydroxylase-C(17,20)-lyase (P450(17 alpha)). Potent inhibitors of this enzyme could be of value as treatment of prostate cancer. Two substituents (methyl and phenyl) were introduced either at their 4'- or 5'-position in order to investigate their structure-activity relationship. Due to the 16,17-double bond, 17-thiazoles were generally obtained in low yield. The pharmacological results showed that the compounds containing 17-(2'-oxazolyl) (14c) and 17-(2'-thiazolyl) (8c) (41.5%) demonstrated reasonable inhibition against P450(17 alpha). Their 3-acetate (13c and 7c) were less potent than their 3-OH counterparts. The introduction of a phenyl or methyl group generally decreased inhibitory activity. Surprisingly, 17-(5'-methyl-2'-thiazolyl) (12a) was the most potent compound in this series and was almost as potent as L-39, which has good antitumor activity.