Termination of development of D0870

Williams, Keith; Denning, David W.

doi:10.1093/oxfordjournals.jac.a002691

Cited by 10 publications

(4 citation statements)

References 4 publications

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“…Unfortunately, AstraZeneca, a proprietary biopharmaceutical company, interrupted the development of this compound because D0870 promoted QT prolongation at modest serum concentrations and led to adverse cardiac events in a HIV-positive patient receiving the drug for fluconazole-resistant oropharyngeal and esophageal candidiasis. 140 …”

Section: Methodsmentioning

confidence: 99%

Experimental and Clinical Treatment of Chagas Disease: A Review

Sales

Molina

Murta

et al. 2017

The American Journal of Tropical Medicine and Hygiene

242

170

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Abstract.Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed. Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.

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Section: Methodsmentioning

confidence: 99%

Experimental and Clinical Treatment of Chagas Disease: A Review

Sales

Molina

Murta

et al. 2017

The American Journal of Tropical Medicine and Hygiene

242

170

View full text Add to dashboard Cite

show abstract

“…The experimental azole drug, D0870 was the first to show cure of mice chronically infected with T. cruzi (Urbina et al 1996a). Unfortunately, D0870 was discontinued in clinical trials (of fungal infections) due to untoward side effects (Williams and Denning ,2001). The second-generation azole antifungal drug, voriconazole, has comparatively weak anti- T. cruzi activity (Buckner ,2008) and has not been pursued for clinical development.…”

Section: History Of Azole Drug Testing On T Cruzimentioning

confidence: 99%

Recent developments in sterol 14-demethylase inhibitors for Chagas disease

Buckner

Urbina

2012

International Journal for Parasitology: Drugs and Drug Resistan

101

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The protozoan parasite, Trypanosoma cruzi, causes the most prevalent parasitic infection in the American continent. It gives rise to life-long infection in humans and results in severe cardiomyopathy or other life-threatening manifestations (Chagas disease) in ~30% of those infected. Animal models and clinical studies indicate that etiological treatment of the infection reduces the risk of developing the disease manifestations. Unfortunately, the existing chemotherapeutics have suboptimal antiparasitic activity and cause significant side effects in many patients, thus better anti-trypanosomal drugs are greatly needed. The sterol biosynthesis pathway has received attention as a target for the development of new drugs for Chagas disease. In particular, inhibitors of sterol 14-demethylase (CYP51) are shown to be extremely active on Trypanosoma cruzi in vitro and in animal models. Antifungal drugs (i.e. azoles) in clinical use or in clinical studies have been extensively tested preclinically on Trypanosoma cruzi with posaconazole and ravuconazole demonstrating the most promising activity. As a result, posaconazole and a pro-drug of ravuconazole (E1224) are currently being evaluated in Phase II studies for Chagas disease. Additional CYP51 inhibitors that are specifically optimized for anti-Trypanosoma cruzi activity are in development by academia. These represent an alternative to proprietary antifungal drugs if the latter fall short in clinical trials or are too expensive for widespread clinical use in disease endemic countries. The research over the next few years will help define the role of CYP51 inhibitors, alone or in combination with other drugs, for managing patients with Chagas disease.

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“…Most potent of them, D0870, cured both short- and long-term experimental Chagas disease in mice [63], yet unfortunately failed in clinical trials as an antifungal drug due to cardiotoxicity (inhibitory effect on the hERG channel causing QTc prolongation [64]). Finally, in 2012, posaconazole (the derivative of itraconazole) and ravuconazole (the derivative of voriconazole) entered clinical trials for Chagas disease in Spain, Bolivia and Argentina.…”

Section: Screening Of Existing Antifungal Drugsmentioning

confidence: 99%

Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

Lepesheva

2013

Expert Opinion on Drug Discovery

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Introduction Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) – posaconazole and ravuconazole – entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation. Areas covered This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs. Expert opinion There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs.

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Termination of development of D0870

Cited by 10 publications

References 4 publications

Experimental and Clinical Treatment of Chagas Disease: A Review

Experimental and Clinical Treatment of Chagas Disease: A Review

Recent developments in sterol 14-demethylase inhibitors for Chagas disease

Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

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