Sordarin derivatives represent a new class of
antifungal agents that act as potent inhibitors of fungal
protein synthesis and possess a broad spectrum of activity. The in vivo activity of
GM193663 and
GM237354 was studied in mouse models of disseminated
candidiasis and
aspergillosis and in a rat model of
pneumocystosis. The pharmacokinetic behavior of both
sordarin derivatives was studied in mice and rats. In all studies, compounds were administered by the subcutaneous route. After a subcutaneous dose of 50 mg/kg of
body weight to mice, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for
GM193663 and
GM237354 were 51.8 and 23 microg/ml, 79.5 and 46 microg. h/ml, 0.8 and 0.85 h, and 21 and 25 ml/h, respectively.
Systemic candidiasis and
aspergillosis were established in CD-1 male mice infected with Candida albicans or Aspergillus fumigatus. For
systemic candidiasis, compounds were given three times per day for seven consecutive days at 15, 30, 60, or 120 mg/kg/day.
GM193663 and
GM237354 showed dose-related efficacy against C. albicans, with 50% effective doses, 1 month after
infection, of 25.2 and 10.7 mg/kg/dose, respectively. In experimental
infections with A. fumigatus,
GM237354 was given three times per day at 30, 60, or 120 mg/kg/day for five consecutive days. Animals treated with
GM237354 demonstrated irregular responses. The survival of animals treated with
GM237354 was 0, 30, and 0% at 30, 60, and 120 mg/kg/day, respectively. The therapeutic efficacy of
GM193663 and
GM237354 against Pneumocystis carinii was studied in an experimental P. carinii
pneumonia (PCP) rat model. After a subcutaneous dose of 10 mg/kg given to rats, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for
GM193663 and
GM237354 were 6.6 and 7.2 microg/ml, 8.5 and 11.8 microg. h/ml, 0.7 and 0.8 h, and 230 and 133 ml/h, respectively. To induce spontaneous PCP, rats were chronically immunosuppressed with
dexamethasone. Infected animals were treated twice daily for 10 days at 0.2, 2, or 10 mg/kg/day. The
therapeutic effect was estimated by the reduction in the number of
cysts in the lungs of treated versus untreated animals.
GM193663 and
GM237354 significantly reduced the mean (+/- standard deviation) log number of
cysts from 7.6 +/- 0.2 in the untreated group to 4.7 +/- 0.2 and 4.6 +/- 0.1, respectively, when the drugs were administered at a dose of 2 mg/kg/day. The log number of
cysts was also reduced in infected animals given lower doses of the compounds (0.2 mg/kg/day). In summary,
GM193663 and
GM237354 are new
sordarin derivatives that may potentially play a major role in the treatment of
candidiasis and PCP. Further testing with Aspergillus in other animal models is warranted.