ArticleJournal of medicinal chemistry2019
Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.
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Article in Journal of medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 49 citations in OpenAlex.
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- Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis.Journal of medicinal chemistry · 2021Article
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Authors and funding
52 authors at 5 institutions in 5 countries.
Michael G ThomasDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Manu De RyckerDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.ORCID 0000-0002-3171-3519
Myriam AjakaneCellzome GmbH , A GlaxoSmithKline Company , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.
Sébastian AlbrechtDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Ana Isabel Álvarez-PedraglioGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Markus BoescheCellzome GmbH , A GlaxoSmithKline Company , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.
Stephen BrandDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Lorna CampbellDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Juan Cantizani-PerezGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Laura A T CleghornDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Royston C B CopleyPlatform Technology & Science , GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
Sabrinia D CrouchGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Alain DauganCentre de Recherche , GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec , 91140 Villebon sur Yvette France.
Gerard DrewesCellzome GmbH , A GlaxoSmithKline Company , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.
Santiago FerrerGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Sonja Ghidelli-DisseCellzome GmbH , A GlaxoSmithKline Company , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.
Silvia GonzalezGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Stephanie L GreshamPlatform Technology & Science , GlaxoSmithKline , David Jack Centre for R&D, Park Road , Ware , Hertfordshire SG12 0DP , U.K.
Alan P HillPlatform Technology & Science , GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
Sean J HindleyPlatform Technology & Science , GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
Rhiannon M LowePlatform Technology & Science , GlaxoSmithKline , David Jack Centre for R&D, Park Road , Ware , Hertfordshire SG12 0DP , U.K.
Claire J MacKenzieDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Lorna MacLeanDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Sujatha ManthriDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Franck MartinCentre de Recherche , GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec , 91140 Villebon sur Yvette France.
Juan Miguel-SilesGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Van Loc NguyenCentre de Recherche , GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec , 91140 Villebon sur Yvette France.
Suzanne NorvalDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Maria Osuna-CabelloDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Andrew WoodlandDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Stephen PattersonDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Imanol PenaGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Maria Teresa Quesada-CamposGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Iain H ReidPlatform Technology & Science , GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
Charlotte RevillDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Jennifer RileyDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Jose Ramon Ruiz-GomezGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Yoko ShishikuraDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Frederick R C SimeonsDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Alasdair SmithDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Victoria C SmithDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Daniel SpinksDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Laste StojanovskiDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
John ThomasDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Stephen ThompsonDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Tim UnderwoodPlatform Technology & Science , GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
David W GrayDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.
Jose M FiandorGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.
Ian H GilbertDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.ORCID 0000-0002-5238-1314
Paul G WyattDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.ORCID 0000-0002-0397-245X
Kevin D ReadDrug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , Dundee DD1 5EH , U.K.ORCID 0000-0002-8536-0130
Timothy J MilesGlobal Health R&D , GlaxoSmithKline , Calle Severo Ochoa, 2 , 28760 Tres Cantos , Madrid Spain.ORCID 0000-0001-7407-7404
Discovery Centre · CAGlaxoSmithKline (Spain) · ESGlaxoSmithKline (United Kingdom) · GBGlaxoSmithKline (Germany) · DEGlaxoSmithKline (France) · FR
Funding
Wellcome Trust 092340Wellcome Trust 100476Wellcome Trust 203134Wellcome Trust 203134/Z/16/ZWellcome Trust 204672/Z/16/Z
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.
Indexed as
AnimalsFemaleHep G2 CellsHumansLeishmania donovaniLeishmaniasis, VisceralMaleMice, Inbred BALB CMolecular StructureMorpholinesParasitic Sensitivity TestsProtein Kinase InhibitorsPyrazolesPyrimidinesRats, Sprague-DawleyStructure-Activity RelationshipGSK3186899MorpholinesProtein Kinase InhibitorsPyrazolesPyrimidinesTrypanocidal Agents
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