title: In vitro and in vivo antifungal activities of TAK-456, a novel oral triazole with a broad antifungal spectrum.
abstract: TAK-456 is a novel oral triazole compound with potent and broad-spectrum in vitro antifungal activity and strong in vivo efficacy against Candida albicans and Aspergillus fumigatus. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50% at 3 to 11 ng/ml. TAK-456 showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and Cryptococcus neoformans, except for Candida glabrata. The MICs at which 90% of the isolates tested were inhibited byTAK-456, fluconazole, itraconazole, voriconazole, and amphotericin B were 0.25, 4, 0.5, 0.13, and 0.5 microg/ml, respectively, for clinical isolates of C. albicans and 1, >64, 0.5, 0.5, and 0.5 microg/ml, respectively, for clinical isolates of A. fumigatus. Therapeutic activities of TAK-456 and reference triazoles against systemic lethal infections caused by C. albicans and A. fumigatus in mice were investigated by orally administering drugs once daily for 5 days, and efficacies of the compounds were evaluated by the prolongation of survival. In normal mice, TAK-456 and fluconazole were effective against infection caused by fluconazole-susceptible C. albicans at a dose of 1 mg/kg. In transiently neutropenic mice, therapeutic activity of TAK-456 at 1 mg/kg of body weight against infection with the same strain was stronger than those at 1 mg/kg of fluconazole. TAK-456 was effective against infections with two strains of fluconazole-resistant C. albicans at a dose of 10 mg/kg. TAK-456 also expressed activities similar to or higher than those of itraconazole against the infections caused by two strains of A. fumigatus in neutropenic mice at a dose of 10 mg/kg. These results suggest that TAK-456 is a promising candidate for development for the treatment of candidiasis and aspergillosis in humans.
authors.affiliation: Pharmacology Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Tsuchimori_Noboru@takeda.co.jp
authors.forename: Noboru
authors.initials: N
authors.lastname: Tsuchimori
authors.forename: Ryogo
authors.initials: R
authors.lastname: Hayashi
authors.forename: Naomi
authors.initials: N
authors.lastname: Kitamoto
authors.forename: Kentaro
authors.initials: K
authors.lastname: Asai
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kitazaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iizawa
authors.forename: Katsumi
authors.initials: K
authors.lastname: Itoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Okonogi
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects; D005260:Female; D005658:Fungi / Q000187:drug effects*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008826:Microbial Sensitivity Tests; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D007093:Imidazoles; C423467:TAK 456; D013777:Tetrazoles