C_17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C_17,20-lyase inhibitors

A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C_17,20-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C_17,20-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C _17,20-lyase over 11β-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.