Wyllie S, Thomas M, Patterson S, Crouch S, De Rycker M, Lowe R, Gresham S, Urbaniak MD, Otto TD, Stojanovski L, Simeons FRC, Manthri S, MacLean LM, Zuccotto F, Homeyer N, Pflaumer H, Boesche M, Sastry L, Connolly P, Albrecht S, Berriman M, Drewes G, Gray DW, Ghidelli-Disse S, Dixon S, Fiandor JM, Wyatt PG, Ferguson MAJ, Fairlamb AH, Miles TJ, Read KD, Gilbert IH.
Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.