In vitro and in vivo activities of SCH 42427, the active enantiomer of the antifungal agent SCH 39304.
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.
Loebenberg
D
D
Schering-Plough Research, Bloomfield, New Jersey 07003.
Cacciapuoti
A
A
Parmegiani
R
R
Moss
E L
EL
Menzel
F
F
Antonacci
B
B
Norris
C
C
Yarosh-Tomaine
T
T
Hare
R S
RS
Miller
G H
GH
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
D000935:Antifungal Agents; D014230:Triazoles; C056513:Sch 39304