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DOI 10.1021/acs.jmedchem.8b01218

Медицинская библиотека · Journal of medicinal chemistry · 2018

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

Thomas Michael G, De Rycker Manu, Ajakane Myriam, Albrecht Sébastian, Álvarez-Pedraglio Ana Isabel, Boesche Markus, Brand Stephen, Campbell Lorna, Cantizani-Perez Juan, Cleghorn Laura A T, Copley Royston C B, Crouch Sabrinia D, Daugan Alain, Drewes Gerard, Ferrer Santiago, Ghidelli-Disse Sonja, Gonzalez Silvia, Gresham Stephanie L, Hill Alan P, Hindley Sean J, Lowe Rhiannon M, MacKenzie Claire J, MacLean Lorna, Manthri Sujatha, Martin Franck, Miguel-Siles Juan, Nguyen Van Loc, Norval Suzanne, Osuna-Cabello Maria, Woodland Andrew, Patterson Stephen, Pena Imanol, Quesada-Campos Maria Teresa, Reid Iain H, Revill Charlotte, Riley Jennifer, Ruiz-Gomez Jose Ramon, Shishikura Yoko, Simeons Frederick R C, Smith Alasdair, Smith Victoria C, Spinks Daniel, Stojanovski Laste, Thomas John, Thompson Stephen, Underwood Tim, Gray David W, Fiandor Jose M, Gilbert Ian H, Wyatt Paul G, Read Kevin D, Miles Timothy J

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Аннотация

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.

Для цитирования: Thomas Michael G, De Rycker Manu, Ajakane Myriam, Albrecht Sébastian, Álvarez-Pedraglio Ana Isabel, Boesche Markus, Brand Stephen, Campbell Lorna, Cantizani-Perez Juan, Cleghorn Laura A T, Copley Royston C B, Crouch Sabrinia D, Daugan Alain, Drewes Gerard, Ferrer Santiago, Ghidelli-Disse Sonja, Gonzalez Silvia, Gresham Stephanie L, Hill Alan P, Hindley Sean J, Lowe Rhiannon M, MacKenzie Claire J, MacLean Lorna, Manthri Sujatha, Martin Franck, Miguel-Siles Juan, Nguyen Van Loc, Norval Suzanne, Osuna-Cabello Maria, Woodland Andrew, Patterson Stephen, Pena Imanol, Quesada-Campos Maria Teresa, Reid Iain H, Revill Charlotte, Riley Jennifer, Ruiz-Gomez Jose Ramon, Shishikura Yoko, Simeons Frederick R C, Smith Alasdair, Smith Victoria C, Spinks Daniel, Stojanovski Laste, Thomas John, Thompson Stephen, Underwood Tim, Gray David W, Fiandor Jose M, Gilbert Ian H, Wyatt Paul G, Read Kevin D, Miles Timothy J. Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.. Journal of medicinal chemistry. 2018. DOI: 10.1021/acs.jmedchem.8b01218.

Предметные рубрики MeSH

AnimalsFemaleHep G2 CellsHumansLeishmania donovaniLeishmaniasis, VisceralMaleMice, Inbred BALB CMolecular StructureMorpholinesParasitic Sensitivity TestsProtein Kinase InhibitorsPyrazolesPyrimidinesRats, Sprague-DawleyStructure-Activity RelationshipTrypanocidal Agents
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