17-IMIDAZOLYL, PYRAZOLYL, AND ISOXAZOLYL ANDROSTENE DERIVATIVES - NOVEL STEROIDAL INHIBITORS OF HUMAN CYTOCHROME C-17,C-20-LYASE (P450(17-ALPHA))

We recently described a number of inhibitors of P450(17 alpha), the ke y enzyme of androgen biosynthesis. Here, we report the synthesis and a ctivity of novel 17-imidazolyl, pyrazolyl, and isoxazolyl androstene d erivatives as potential agents for the treatment of prostatic cancer. A number of 17-(4'-Imidazolyl) derivatives were prepared by condensing the corresponding 17-ketol acetate side chain with aldehyde and ammon ium hydroxide. The 17 beta-(4'-imidazolyl) derivatives (2a, 2e, 4a, 4c ) were found to be potent inhibitors of human testicular P450(17 alpha ), with greater activity than ketoconazole. The juxtaposition between the imidazole ring and the steroid D ring appears to be important in c ontributing inhibitory properties. Compounds having a 17 beta-(2'-imid azolyl) ring (9a, 10) or a 20 beta-(2'-imidazolyl) ring (12), instead of the 17 beta-(4'-imidazolyl) ring (2a, 4a), are weak inhibitors. Amo ng the 17-(4'-imidazolyl) derivatives, introduction of the 17 alpha-hy droxy group (4b) and 16 alpha,17 alpha-epoxide group (2d) diminished p otency (2a --> 2d; IC50 66 --> 430 nM; 4 --> 4b; IC50 58 --> 1200 nM), while the 16,17 double bond increased the inhibitory activity by almo st three times in the 5-en-3 beta-ol inhibitors (2a --> 2e; IC50 66 -- > 24 nM). There was virtually no difference in the inhibitory activity in the 4-en-3-one inhibitors (4a --> 4c; IC50 58 --> 50 nM). The intr oduction of a methyl (2b) or phenyl group (2c) on the 2'-position of 4 '-imidazolyl ring caused a dramatic decrease in the potency. As to mod ification of the A,B rings, the 3-acetate (2f, 2g) decreased the poten cy almost 3-fold compared with the 3-alcohol (2e --> 2f, IC50 24 --> 7 5 nM; 2a --> 2g, 66 --> 199 nM) and the conversion from the 5-en-3 bet a-ol into the 4-en-3-one hardly affected the potency. As expected, 4c was more potent than 2e for the rat P450(17 alpha). 17-(3'-Pyrazolyl)- (14b) and 17-(5'-isoxazolyl)-androsta-5,16-dien-3 beta-ol (15b) were also potent inhibitors of P450(17 alpha), whereas the 17-(2'-imidazoly l) compound (9b) was one of the most potent inhibitor in this series. However, their 16-saturated counterparts (9a, 14a, 15a) were weak inhi bitors. The 17 beta-(3'-isoxazolyl)- (16) and 17 beta-(5'-methyl-3'-ox azolyl)androst-5-en-3 beta-ol (18) were also inactive. The introductio n of a methyl or phenyl group on the nitrogen of the pyrazolyl ring of 14b [see 14c, 14d, and 14c] also caused some loss of inhibition for P 450(17 alpha). Compounds 2e, 4a, 4c, 9b, 14b, 17a and 17b are among th e most potent inhibitors of human P450(17 alpha) so far reported.