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

J Med Chem. 2019 Feb 14;62(3):1180-1202. doi: 10.1021/acs.jmedchem.8b01218. Epub 2018 Dec 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Hep G2 Cells
  • Humans
  • Leishmania donovani / drug effects
  • Leishmaniasis, Visceral / drug therapy*
  • Male
  • Mice, Inbred BALB C
  • Molecular Structure
  • Morpholines / chemical synthesis
  • Morpholines / therapeutic use*
  • Morpholines / toxicity
  • Parasitic Sensitivity Tests
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinase Inhibitors / toxicity
  • Pyrazoles / chemical synthesis
  • Pyrazoles / therapeutic use*
  • Pyrazoles / toxicity
  • Pyrimidines / chemical synthesis
  • Pyrimidines / therapeutic use*
  • Pyrimidines / toxicity
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / therapeutic use*
  • Trypanocidal Agents / toxicity

Substances

  • GSK3186899
  • Morpholines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Trypanocidal Agents