title: Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone.
abstract: 1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Ichikawa_Takashi@takeda.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Ichikawa
authors.forename: T
authors.initials: T
authors.lastname: Kitazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Matsushita
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: R
authors.initials: R
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Kiyota
authors.forename: K
authors.initials: K
authors.lastname: Okonogi
authors.forename: K
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000478:Alkylation; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000187:drug effects; D001393:Azoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D006207:Half-Life; D006461:Hemolysis / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012995:Solubility; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D007093:Imidazoles; D011355:Prodrugs; C423467:TAK 456; D013777:Tetrazoles