Abstract
ABSTRACTThe profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.
Highlights
The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies
Site of infection tend to be lower than those in other, healthy organs. This is especially so for the liver, which is a site of triazole toxicity: up to 15% of patients treated with voriconazole experience raised transaminase levels [6, 7]
PC945 produced type II difference spectra when titrated against purified Aspergillus fumigatus CYP51A and CYP51B enzymes (AfCYP51A and AfCYP51B) and bound to CYP51A with an affinity similar to that of posaconazole (Table 1; Fig. 1B)
Summary
The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 g/mouse, while posaconazole showed similar effects (44%) at 14 g/ mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung. Existing antifungal medicines are predominantly dosed either orally or systemically These frequently exploited routes of delivery are poor for treating airway disease, since drug concentrations achieved at the. We disclose the in vitro and in vivo activity of PC945, which has the chemical formula 4-[4-(4-{[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)oxolan-3yl]methoxy}-3-methylphenyl)piperazin-1-yl]-N-(4-fluorophenyl)benzamide (Fig. 1A) and is a novel triazole antifungal agent designed for inhaled administration [10]
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