Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

Michael G. Thomas, Manu De Rycker, Myriam Ajakane, Sébastian Albrecht, Ana Isabel Álvarez-Pedraglio, Markus Boesche, Stephen Brand, Lorna Campbell, Juan Cantizani-Perez, Laura A.T. Cleghorn, Royston C.B. Copley, Sabrinia D. Crouch, Alain Daugan, Gerard Drewes, Santiago Ferrer, Sonja Ghidelli-Disse, Silvia Gonzalez, Stephanie L. Gresham, Alan P. Hill, Sean J. Hindley, Rhiannon M. Lowe, Claire J. MacKenzie, Lorna MacLean, Sujatha Manthri, Franck Martin, Juan Miguel-Siles, Van Loc Nguyen, Suzanne Norval, Maria Osuna-Cabello, Andrew Woodland, Stephen Patterson, Imanol Pena, Maria Teresa Quesada-Campos, Iain H. Reid, Charlotte Revill, Jennifer Riley, Jose Ramon Ruiz-Gomez, Yoko Shishikura, Frederick R.C. Simeons, Alasdair Smith, Victoria C. Smith, Daniel Spinks, Laste Stojanovski, John Thomas, Stephen Thompson, Tim Underwood, David W. Gray, Jose M. Fiandor, Ian H. Gilbert , Paul G. Wyatt , Kevin D. Read , and Timothy J. Miles

Journal Medicinal Chemistry DOI10.1021/acs.jmedchem.8b01218

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651  for VL.