1. Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.
- Author
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Thomas MG, De Rycker M, Ajakane M, Albrecht S, Álvarez-Pedraglio AI, Boesche M, Brand S, Campbell L, Cantizani-Perez J, Cleghorn LAT, Copley RCB, Crouch SD, Daugan A, Drewes G, Ferrer S, Ghidelli-Disse S, Gonzalez S, Gresham SL, Hill AP, Hindley SJ, Lowe RM, MacKenzie CJ, MacLean L, Manthri S, Martin F, Miguel-Siles J, Nguyen VL, Norval S, Osuna-Cabello M, Woodland A, Patterson S, Pena I, Quesada-Campos MT, Reid IH, Revill C, Riley J, Ruiz-Gomez JR, Shishikura Y, Simeons FRC, Smith A, Smith VC, Spinks D, Stojanovski L, Thomas J, Thompson S, Underwood T, Gray DW, Fiandor JM, Gilbert IH, Wyatt PG, Read KD, and Miles TJ
- Subjects
- Animals, Female, Hep G2 Cells, Humans, Leishmania donovani drug effects, Male, Mice, Inbred BALB C, Molecular Structure, Morpholines chemical synthesis, Morpholines toxicity, Parasitic Sensitivity Tests, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors toxicity, Pyrazoles chemical synthesis, Pyrazoles toxicity, Pyrimidines chemical synthesis, Pyrimidines toxicity, Rats, Sprague-Dawley, Structure-Activity Relationship, Trypanocidal Agents chemical synthesis, Trypanocidal Agents toxicity, Leishmaniasis, Visceral drug therapy, Morpholines therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Trypanocidal Agents therapeutic use
- 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.
- Published
- 2019
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