title: In vitro and in vivo antifungal activities of aminopiperidine derivatives, novel ergosterol synthesis inhibitors.
abstract: Aminopiperidine derivatives, Compound 1a and 1b, are novel small molecules that inhibit C-14 reduction catalyzed by Erg24p in ergosterol synthesis of Candida albicans. We evaluated the properties of the in vitro and in vivo activities of these compounds against pathogenic fungi and compared their activities with those of fluconazole. Compound 1a and 1b exhibited potent in vitro activities against clinically important fungi such as Candida species, including both of fluconazole-resistant strains of C. albicans and non-albicans Candida, Aspergillus fumigatus, and Cryptococcus neoformans. Against C. albicans, its mode of action was fungistatic. Furthermore, orally administered Compound 1b clearly prolonged the survival of infected mice in systemic lethal infection caused by C. albicans. These results suggest that aminopiperidine derivative is a promising lead compound for an orally available novel antifungal drug with a broad spectrum.
authors.affiliation: Biological Research Laboratory IV, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo134-8630, Japan. hata.masato.tu@daiichisankyo.co.jp
authors.forename: Masato
authors.initials: M
authors.lastname: Hata
authors.forename: Kumi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Chiaki
authors.initials: C
authors.lastname: Ishii
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Otani
authors.forename: Akikazu
authors.initials: A
authors.lastname: Ando
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D004875:Ergosterol / Q000037:antagonists & inhibitors*; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D010880:Piperidines; D015725:Fluconazole; D004875:Ergosterol