Stéphanie Braillard , Martine Keenan, Karen J. Breese, Jacob Heppell, Michael Abbott, Rafiqul Islam, David M. Shackleford, Kasiram Katneni, Elly Crighton, Gong Chen, Rahul Patil, Given Lee, Karen L. White, Sandra Carvalho, Richard J. Wall, Giulia Chemi, Fabio Zuccotto, Silvia González, Maria Marco, Julianna Deakyne, David Standing, Gino Brunori, Jonathan J. Lyon, Pablo Castañeda-Casado, Isabel Camino, Maria S. Martinez Martinez, Bilal Zulfiqar, Vicky M. Avery, Pim-Bart Feijens, Natascha Van Pelt An Matheeussen, Sarah Hendrickx, Louis Maes, Guy Caljon Vanessa Yardley, Susan Wyllie , Susan A. Charman, and Eric Chatelain.
Science Translational Medicine 2023. vol 15,no. 726. DOI: 10.1126/scitranslmed.adh9902
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.