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.
Highlights
Kinetoplastid diseases are part of the list of the neglected tropical diseases (NTDs) as defined by the World Health Organisation (WHO).[1]
This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of visceral leishmaniasis (VL)
We previously reported that diaminothiazole 2 demonstrated activity against the related parasite Trypanosoma brucei,[18] and that a scaffold-hopping strategy identified pyrazolopyrimidine 3 as having very weak activity against L. donovani (Ld) axenic amastigotes,[17] albeit with no activity against intracellular parasites
Summary
Kinetoplastid diseases are part of the list of the neglected tropical diseases (NTDs) as defined by the World Health Organisation (WHO).[1]. Discovery Unit, University of Dundee and GSK (funded by Wellcome), has been to identify safe, effective, oral, and shortcourse (ideally ≤10 days) drug candidates for VL, in line with the DNDi (Drugs for Neglected Disease initiative) target product profile.[9] the focus was to identify orally available compounds that demonstrate both in vitro and in vivo parasite suppression comparable to miltefosine (the only available oral therapy) in preclinical models, with an appropriate safety profile This strategy of focusing on parasite suppression has been used successfully for discovery of most of the current protozoan chemotherapies.[10] Because there are very few fully validated druggable targets in the kinetoplastids, most groups have focused on phenotypic approaches.[11,12]. This effort led to the in vivo profiling of a number of analogues, and the identification of precandidate asset GSK3186899/DDD853651, 1(Figure 2).[16,17] Subsequent target deconvolution identified that the principal target was Cdc2-related kinase 12 (CRK12),[17] this was unknown during the lead optimization program
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