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.
Subject(s)
Leishmaniasis, Visceral/drug therapy , Morpholines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Trypanocidal Agents/therapeutic use , 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/toxicityABSTRACT
Identification of compounds that target metabolically diverse subpopulations of Mycobacterium tuberculosis (Mtb) may contribute to shortening the course of treatment for tuberculosis. This study screened 270,000 compounds from GlaxoSmithKline's collection against Mtb in a nonreplicating (NR) state imposed in vitro by a combination of four host-relevant stresses. Evaluation of 166 confirmed hits led to detailed characterization of 19 compounds for potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds depended on reactive nitrogen species for selective activity against NR Mtb, and two were stable in the assay conditions. Four novel scaffolds with activity against replicating (R) Mtb were also identified. However, none of the 19 compounds was active against Mtb in both NR and R states. There was minimal overlap between compounds found active against NR Mtb and those previously identified as active against R Mtb, supporting the hypothesis that NR Mtb depends on distinct metabolic pathways for survival.
