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

authors

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

publication date

  • February 2019

issue

  • 3

volume

  • 62

International Standard Serial Number (ISSN)

  • 0022-2623

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

abstract

  • 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 (1) for VL.