The search for new triazole antifungal agents

Koltin, Y.; Hitchcock, Christopher A.

doi:10.1016/s1367-5931(97)80007-5

Cited by 108 publications

(83 citation statements)

References 28 publications

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“…The pharmacokinetics of voriconazole has been investigated after single and multiple doses in healthy volunteers (Koltin and Hitchcock, 1997;Sheehan et al, 1999;Purkins et al, 2002). In vitro and in vivo studies indicate that voriconazole is extensively metabolized by the cytochrome P450 system with less than 2% of the dose excreted unchanged (EPAR for Vfend, 2002).…”

mentioning

confidence: 99%

Identification of the Cytochrome P450 Enzymes Involved in theN-Oxidation of Voriconazole

Hyland

Jones²,

Smith³

2003

Drug Metab Dispos

356

335

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mentioning

confidence: 99%

Identification of the Cytochrome P450 Enzymes Involved in theN-Oxidation of Voriconazole

Hyland

Jones²,

Smith³

2003

Drug Metab Dispos

356

335

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“…Posaconazole (SCH 56592) (POC), a new triazole antifungal compound, has a potent and broad spectrum of antifungal activity (24,37,43). POC is structurally similar to the broadspectrum triazole compound itraconazole (ITC) (17).…”

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confidence: 99%

Antifungal Activity and Pharmacokinetics of Posaconazole (SCH 56592) in Treatment and Prevention of Experimental Invasive Pulmonary Aspergillosis: Correlation with Galactomannan Antigenemia

Petraitienė

Petraitis

Groll

et al. 2001

Antimicrob Agents Chemother

160

112

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The antifungal efficacy, safety, and pharmacokinetics of posaconazole (SCH 56592) (POC) were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of POC at 2, 6, and 20 mg/kg of body weight per os; itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (P < 0.01). There was dosage-dependent microbiological clearance of A. fumigatus from lung tissue in response to POC. Serum creatinine levels were greater (P < 0.01) in AMB-treated animals than in UC and POC-or ITC-treated rabbits. There was no elevation of serum hepatic transaminase levels in POC-or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at >6 mg/kg/day per os generated sustained concentrations in plasma of >1 g/ml that were as effective in the treatment and prevention of invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than cyclodextrin ITC at >6 mg/kg/day per os in persistently neutropenic rabbits.

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“…However, the treatment of others is still far from satisfactory, and there is a need for new broad-and narrow-spectrum antifungal agents (3). Furthermore, fungal resistance caused by acquisition of intrinsically resistant species, e.g., Aspergillus fumigatus, or by mutation of initially susceptible strains, e.g., Candida albicans, is an increasing clinical problem (5,6) forcing the development of new triazole antifungals. Azole antifungals selectively inhibit yeast and fungal CYP51 over their plant and human counterparts (7), but crossover inhibition of CYP51 in two different species can cause undesirable side effects and is another reason for the continuing search for better agents (3,8).…”

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confidence: 99%

Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors

Podust

Poulos

Waterman

2001

Proc. Natl. Acad. Sci. U.S.A.

497

403

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-desaturated intermediates in ergosterol (fungi), phytosterol (plants), and cholesterol (animals) biosynthesis. During the catalytic cycle, a substrate undergoes three successive monooxygenation reactions resulting in formation of 14-hydroxymethyl, 14-carboxaldehyde, and 14-formyl derivatives followed by elimination of formic acid with introduction of a 14,15 double bond (1, 2).Being a key enzyme of sterol biosynthesis, CYP51 has been a target for antifungal (3) and cholesterol-lowering (4) drug design. The first generation of antifungal inhibitors of CYP51, fluconazole (FLU) and itraconazole, have revolutionized treatment of some serious fungal infections. However, the treatment of others is still far from satisfactory, and there is a need for new broad-and narrow-spectrum antifungal agents (3). Furthermore, fungal resistance caused by acquisition of intrinsically resistant species, e.g., Aspergillus fumigatus, or by mutation of initially susceptible strains, e.g., Candida albicans, is an increasing clinical problem (5, 6) forcing the development of new triazole antifungals. Azole antifungals selectively inhibit yeast and fungal CYP51 over their plant and human counterparts (7), but crossover inhibition of CYP51 in two different species can cause undesirable side effects and is another reason for the continuing search for better agents (3,8). The problem of specificity is being addressed empirically by exploring inhibitors of different structures and by efforts to develop threedimensional molecular models of CYP51-active sites based on primary sequence analyses and available structures for bacterial P450s. These models initially were based on the structure of P450cam (9, 10) and more recently on the structure of P450BM3 (11-14) because of its higher sequence similarity.The available P450 structures show that the overall P450 structural fold is preserved during evolution from bacteria through mammals (15)(16)(17)(18)(19)(20)(21)(22). At the same time, there are variable regions that appear to be associated with recognition and binding of structurally diverse substrates and redox partners (23). Experimental structural information on the active sites of the fungal, plant, and mammalian CYP51 would greatly facilitate developing more efficacious antifungal drugs. However, until recently all known forms of CYP51 were membrane-bound microsomal enzymes, which complicated structural studies of this protein by x-ray crystallography. A soluble CYP51 ortholog discovered recently in Mycobacterium tuberculosis (24) exhibits 35-38% sequence identity to plant, 33-35% to animal, and 26-29% to fungal enzymes. Although MTCYP51 can oxidize lanosterol and 24,25-dihydrolanosterol in vitro, the plant substrate obtusifoliol is preferred (25). We have crystallized Escherichia coli-expressed MTCYP51 in the presence of two different azole inhibitors, 4-phenylimidazole (4-PI) and FLU, and report here their structures at 2.1 and 2.2 Å, respectively. Materials and MethodsMTCYP51 was expressed and purified as described (25). Protein of appro...

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The search for new triazole antifungal agents

Cited by 108 publications

References 28 publications

Identification of the Cytochrome P450 Enzymes Involved in theN-Oxidation of Voriconazole

Identification of the Cytochrome P450 Enzymes Involved in theN-Oxidation of Voriconazole

Antifungal Activity and Pharmacokinetics of Posaconazole (SCH 56592) in Treatment and Prevention of Experimental Invasive Pulmonary Aspergillosis: Correlation with Galactomannan Antigenemia

Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors

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