RO 09-1470 IS A SELECTIVE INHIBITOR OF P-450 LANOSTEROL C-14 DEMETHYLASE OF FUNGI

Ro 09-1470 is a new antifungal agent that belongs to a series of compounds characterized by a tetrahydropyran skeleton with glycine and alkenyl side chains and that inhibits P-450 lanosterol C-14 demethylase (P-450(14DM)) of fungi (Y. Aoki, T. Yamataki, M. Kondoh, Y. Sudoh, N. Nakayama, Y. Sekine, H. Shimada, and M. Arisawa, J. Antibiot. 45:160 170, 1992; S. Matsukuma, T. Ohtsuka, H. Kotaki, H. Sawairi, T. Sane, K. Watanabe, N. Nakayama, Y. Itezono, M. Fujiu, N. Shimma, K. Yok;ose, and T. Okuda, J. Antibiot. 45:151-159, 1992). We have studied the compound's mode of interaction with fungal P-450(14DM) and its selectivity for the fungal versus mammalian P-450 enzymes. Ro 09-1470 bound to the Saccharomyces cerevisiae P-450(14DM) by coordinating to the heme with one-to-one stoichiometry. Unlike the azole compounds, it interacted with both ferric and ferrous heme. It was active also against the P-450(14DM) of Candida albicans. Ro 09-1470 preferentially inhibited the yeast P-450(14DM), showing a 50% inhibitory concentration (IC50) of 0.47 to similar to 1.1 mu M, which is much lower than the IC(50)s for rat hepatic P-450s catalyzing cholesterol biosynthesis (IC50 = 341 mu M), O-nitroanisol O-demethylation (> 1,000 mu M), aniline hydroxylation (> 1,000 mu M), and aminopyrine N-demethylation (920 mu M) The degree of selectivity for yeast P-450 was higher than that of ketoconazole.