title: In vitro and in vivo activities of SCH 42427, the active enantiomer of the antifungal agent SCH 39304.
abstract: SCH 39304, a new triazole antifungal agent, is a 50:50 racemic mixture of two enantiomers, SCH 42427 and SCH 42426. The activities of these three compounds were compared in a series of in vitro and in vivo experiments. SCH 42427 was twofold more active in vitro against a variety of yeasts and dermatophytes than SCH 39304, while SCH 42426 was inactive (MICs greater than 64 micrograms/ml). In a systemic Candida albicans infection in mice, SCH 42427 administered orally (p.o.) (50% protective dose [PD50], 0.17 mg/kg of body weight; 50% effective dose, [ED50], 0.47 mg/kg) had greater efficacy than SCH 39304 (PD50, 0.21 mg/kg; ED50, 0.62 mg/kg) and SCH 42426 (greater than 100 mg/kg for PD50 and ED50). In a pulmonary Aspergillus flavus infection in mice, SCH 42427 p.o. (PD50, 13 mg/kg) was also more effective than SCH 39304 (18 mg/kg) and SCH 42426 (greater than 250 mg/kg). In a C. albicans vaginal infection in hamsters, SCH 42427 p.o. (ED50, 3.5 mg/kg) was more active than SCH 39304 (8.5 mg/kg) and SCH 42426 (320 mg/kg). Following topical administration, against a Trichophyton mentagrophytes infection in guinea pigs, SCH 42427 was about 2-fold more active than SCH 39304 and about 100-fold more active than SCH 42426. These and other results indicated that SCH 42427 is the active enantiomer, responsible for all the antifungal activity observed with SCH 39304.
authors.affiliation: Schering-Plough Research, Bloomfield, New Jersey 07003.
authors.forename: D
authors.initials: D
authors.lastname: Loebenberg
authors.forename: A
authors.initials: A
authors.lastname: Cacciapuoti
authors.forename: R
authors.initials: R
authors.lastname: Parmegiani
authors.forename: E L
authors.initials: EL
authors.lastname: Moss
authors.forename: F
authors.initials: F
authors.lastname: Menzel
authors.forename: B
authors.initials: B
authors.lastname: Antonacci
authors.forename: C
authors.initials: C
authors.lastname: Norris
authors.forename: T
authors.initials: T
authors.lastname: Yarosh-Tomaine
authors.forename: R S
authors.initials: RS
authors.lastname: Hare
authors.forename: G H
authors.initials: GH
authors.lastname: Miller
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D001231:Aspergillus flavus; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D002181:Candidiasis, Vulvovaginal / Q000188:drug therapy / Q000382:microbiology; D006224:Cricetinae; D003881:Dermatomycoses / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D005658:Fungi / Q000187:drug effects*; D006168:Guinea Pigs; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014249:Trichophyton
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C056513:Sch 39304