Novel P45017α inhibitors: 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androstene derivatives

Abstract Twelve 17-(2′-oxazolyl)- and 17-(2′-thiazolyl)-androsta-5,16-diene derivatives were designed and synthesized from 3β-acetoxy-pregna-5,16-dien-20-one ( 1b ) as inhibitors of 17α-hydroxylase-C 17,20 -lyase (P450 17α ). 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 17α . 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.