SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from <0.002 to 0.5 g/ml, and those of itraconazole ranged from <0.008 to 1 g/ml. The SCH 56592 MICs for Candida and Cryptococcus strains ranged from <0.004 to 16 g/ml, and those of fluconazole ranged from <0.062 to >64 g/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus and Aspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD 50 s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD 50 s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD 50 s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistant Candida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD 50 s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD 50 s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against serious Aspergillus or Candida infections.Of the estimated 100,000 known species of fungi, only about 180 have been shown to cause disease in humans, and only about 10% of these are encountered in most clinical settings (8). However, fungal infections have substantially increased over the past two decades, and invasive forms are important causes of morbidity and mortality (2, 16). The major increase in fungal infections is related to increased numbers of immunocompromised patients including those with human immunodeficiency virus infection-AIDS or cancer and bone marrow or solid organ transplant recipients, who are at risk of developing invasive fungal infections (5,7,12,16). Disseminated candidiasis, pulmonary aspergillosis, and mycoses caused by emerging opportunistic fungi are the most common of these serious mycoses (7,16,38). As a result, there is a developing consensus that prophylactic therapy should be used for these high-risk patients (12). Fluconazole (FLC) is used for prevention of fungal infections in some of these patients, but it is not active against Aspergillus or other filamentous fungi. However, there is great concern about the development of resistant Candida due to prophylactic use of FLC (4,10,15,18,23,35,37). Clearly, alternative antifungal agents are needed for both therapeutic and prophylactic use. SCH 56592 (SCH; posaconazole) is a new triazole antifungal agent with broad-spectrum activity against fungi including strains of Aspergillus and Candida resistant to FLC (9,11,19,24,30,33). This report describes the in vitro activity of SCH against Aspergillus and Candida and its efficacy in clinically relevant experimental infection models ...

The echinocandins are a class of semisynthetic natural products that target ␤-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.

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SCH 39304 was compared with fluconazole and ketoconazole in a systemic Candida albicans infection in mice (106 CFU per mouse). Results were based on survival rates and CFU in kidneys following once-daily oral treatment of 2, 5, or 10 days duration. In normal mice, SCH 39304 (dose to reduce kidney counts by 4 log units, 0.5 mg/kg of body weight) was 3 and 200 times more active than fluconazole and ketoconazole, respectively. In immunocompromised mice (gamma irradiation, 600 rads), SCH 39304 (dose to reduce kidney counts by 4 log units, 1.3 mg/kg) was 35 and greater than 100 times more active than fluconazole and ketoconazole, respectively. In normal mice, when the infecting inoculum varied from 105 to 107 CFU, only a fivefold increase in the dose to reduce kidney counts by 4 log units was observed with SCH 39304. Excellent protection was also seen when mice were treated with a single oral dose of SCH 39304 up to 24 h prior to infection with C. albicans. Studies in a systemic C. albicans infection model indicated that SCH 39304 is equally efficacious following either oral or intravenous administration. In a systemic Aspergillusflavus infection, mice treated with SCH 39304 (5 mg/kg) survived twice as long (16 days) as those treated with fluconazole (50 mg/kg) or controls did.

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.