by Braillard S, Keenan M, Breese KJ, Heppell J, Abbott M, Islam R, Shackleford DM, Katneni K, Crighton E, Chen G, Patil R, Lee G, White KL, Carvalho S, Wall RJ, Chemi G, Zuccotto F, González S, Marco M, Deakyne J, Standing D, Brunori G, Lyon JJ, Castañeda-Casado P, Camino I, Martinez MS, Zulfiqar B, Avery VM, Feijens PM, Van Pelt N, Matheeussen A, Hendrickx S, Maes L, Caljon G, Yardley V, Wyllie S, Charman SA, Chatelain E. Science Translational Medicine 2023, 15(726). doi: 10.1126/scitranslmed.adh9902
Summary: New drugs for visceral leishmaniasis that are safe, low cost and adapted to the field are critically needed. Despite substantial effort over the years, the number of new chemical entities ready for development and with new mechanisms of action remains low. In this paper, authors describe the discovery of a new leishmania cytochrome b inhibitor, DNDI-6174, issued from a phenotypically identified pyrrolopyrimidine series that fulfills all DNDi’s target candidate profile criteria to move forward into development. Preclinical studies found that DNDI-6174, the first cytochrome bc1 complex inhibitor to enter preclinical development for leishmaniasis, was potent in vitro against a variety of Leishmania species and able to reduce parasite burden in standard models of infection with a potential for sterile cure, with an adequate pharmacokinetic profile and no safety signals in preliminary safety studies.
