| Autor: |
Braillard, Stéphanie, Keenan, Martine, Breese, Karen J., Heppell, Jacob, Abbott, Michael, Islam, Rafiqul, Shackleford, David M., Katneni, Kasiram, Crighton, Elly, Chen, Gong, Patil, Rahul, Lee, Given, White, Karen L., Carvalho, Sandra, Wall, Richard J., Chemi, Giulia, Zuccotto, Fabio, González, Silvia, Marco, Maria, Deakyne, Julianna |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 12/13/2023, Vol. 15 Issue 726, p1-15, 15p |
| Abstrakt: |
New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis. Editor's summary: Chagas disease (CD) and visceral leishmaniasis are considered neglected tropical diseases and are responsible for ~30,000 fatalities annually. Current treatments for these vector-borne parasitic infections are inadequate, and there is a pressing need for better therapeutics. In companion articles, González et al. and Braillard et al. describe the development of closely related pyrrolopyrimidine compounds that target the cytochrome bc1 complex of the parasite electron transport chain and show promise for the treatment of both diseases. DNDI-6174 demonstrates potent activity in Leishmania models of infection and has a suitable profile for clinical development. For CD, the combination of pyrrolopyrimidine compounds with a subefficacious dose of benznidazole delivers rapid clearance of parasites in an animal model of chronic CD, offering the prospect of safer and shorter treatment regimens. Collectively, these studies represent advances in the development of potential treatments for some of the world's most neglected patient populations. —Christiana Fogg [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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