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Master of Public Health

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc

AUTHORS

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 Martinez MS , Zulfiqar B , Avery VM , Feijens PB , Van Pelt N , Matheeussen A , Hendrickx S , Maes L , Caljon G , Yardley V , Wyllie S , Charman SA , Chatelain E , . Science translational medicine. 2023 12 13; 15(726). eadh9902

ABSTRACT

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 remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of cytochrome bc 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 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 bc complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

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