Search

A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C17,20-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C17,20-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 C17,20-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. [Copyright &y& Elsevier]

To clarify whether nitric oxide (NO) modifies high K+-evoked γ-aminobutyric acid (GABA) release, we examined the effects of sodium nitroprusside, an NO donor; diethyldithiocarbamate, an NO trapper; dithiothreitol, a superoxide radical scavenger; and 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one, a specific guanylyl cyclase inhibitor, on high (100 mM) K+-evoked GABA release from rat hippocampus in vivo using microdialysis. Perfusion with 0.5 or 5 mM sodium nitroprusside significantly reduced high K+-evoked GABA release. Co-perfusion with 0.5 mM sodium nitroprusside and 5 mM diethyldithiocarbamate or 0.5 mM 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one significantly enhanced high K+-evoked GABA release. Co-perfusion with 0.5 mM sodium nitroprusside and 1 mM dithiothreitol tended to increase it. These results demonstrate that sodium nitroprusside reduces high K+-evoked GABA release both via an NO/cyclic GMP-dependent pathway and via an NO-dependent, but cyclic GMP-independent, pathway in rat hippocampus in vivo. [Copyright &y& Elsevier]

An efficient stereocontrolled synthesis of the potent C17,20-lyase inhibitor, (1S)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-2-methyl-1-propanol 1, has been established. The stereogenic center of 1 was successfully constructed by a highly diastereoselective Grignard reaction of 2, while a subsequent imidazole ring annulation afforded 1 in an enantiomerically pure form. The procedure enables a practical synthesis of 1 that can be conveniently carried out on a multigram scale. [Copyright &y& Elsevier]

To clarify whether nitric oxide (NO) modifies high K(+)-evoked gamma-aminobutyric acid (GABA) release, we examined the effects of sodium nitroprusside, an NO donor; diethyldithiocarbamate, an NO trapper; dithiothreitol, a superoxide radical scavenger; and 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one, a specific guanylyl cyclase inhibitor, on high (100 mM) K(+)-evoked GABA release from rat hippocampus in vivo using microdialysis. Perfusion with 0.5 or 5 mM sodium nitroprusside significantly reduced high K(+)-evoked GABA release. Co-perfusion with 0.5 mM sodium nitroprusside and 5 mM diethyldithiocarbamate or 0.5 mM 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one significantly enhanced high K(+)-evoked GABA release. Co-perfusion with 0.5 mM sodium nitroprusside and 1 mM dithiothreitol tended to increase it. These results demonstrate that sodium nitroprusside reduces high K(+)-evoked GABA release both via an NO/cyclic GMP-dependent pathway and via an NO-dependent, but cyclic GMP-independent, pathway in rat hippocampus in vivo.