title: Ro 09-1470 is a selective inhibitor of P-450 lanosterol C-14 demethylase of fungi.
abstract: 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. Yamazaki, 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. Sano, K. Watanabe, N. Nakayama, Y. Itezono, M. Fujiu, N. Shimma, K. Yokose, 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 approximately 1.1 microM, which is much lower than the IC50s for rat hepatic P-450s catalyzing cholesterol biosynthesis (IC50 = 341 microM), p-nitroanisol O-demethylation (> 1,000 microM), aniline hydroxylation (> 1,000 microM), and aminopyrine N-demethylation (920 microM). The degree of selectivity for yeast P-450 was higher than that of ketoconazole.
authors.affiliation: Nippon Roche Research Center, Kamakura, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Aoki
authors.forename: F
authors.initials: F
authors.lastname: Yoshihara
authors.forename: M
authors.initials: M
authors.lastname: Kondoh
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: N
authors.initials: N
authors.lastname: Nakayama
authors.forename: M
authors.initials: M
authors.lastname: Arisawa
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006418:Heme / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011714:Pyrans / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012680:Sensitivity and Specificity; D058886:Sterol 14-Demethylase
chemical_list: D000935:Antifungal Agents; C548417:Cyp51 protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D005656:Fungal Proteins; D011714:Pyrans; C069635:restricticin; D006418:Heme; D002248:Carbon Monoxide; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D007654:Ketoconazole; D005998:Glycine