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Antimicrobial Agents and Chemotherapy, May 2002, p. 1388-1393, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1388-1393.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum

Noboru Tsuchimori,1* Ryogo Hayashi,1 Naomi Kitamoto,1 Kentaro Asai,1 Tomoyuki Kitazaki,2 Yuji Iizawa,1 Katsumi Itoh,3 and Kenji Okonogi4

Pharmacology Research Laboratories II,1 Medicinal Chemistry Research Laboratories I,3 Medicinal Chemistry Research Laboratories II,2 Research Management Department, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan4

Received 7 June 2001/ Returned for modification 25 August 2001/ Accepted 30 January 2002

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 µg/ml, respectively, for clinical isolates of C. albicans and 1, >64, 0.5, 0.5, and 0.5 µg/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.

* Corresponding author. Mailing address: Pharmacology Research Laboratories II, Takeda Chemical Industries, Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Phone: 81-6-6300-6119. Fax: 81-6-6300-6206. E-mail: Tsuchimori_Noboru{at}takeda.co.jp.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1388-1393, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1388-1393.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.





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