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.
| Original language | English |
|---|---|
| Pages (from-to) | 1180-1202 |
| Number of pages | 23 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 62 |
| Issue number | 3 |
| Early online date | 20 Dec 2018 |
| DOIs | |
| Publication status | Published - 14 Feb 2019 |
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Keywords
- Leishmaniasis
- visceral leishmaniasis
- anti-visceral leishmaniasis agents
- Cdc2-related kinase 12 (CRK12) inhibitor
- neglected diseases
Cite this
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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. (Lead / Corresponding author); Read, Kevin D. (Lead / Corresponding author); Miles, Timothy J. (Lead / Corresponding author).
In: Journal of Medicinal Chemistry, Vol. 62, No. 3, 14.02.2019, p. 1180-1202.Research output: Contribution to journal › Article
TY - JOUR
T1 - Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis
AU - Thomas, Michael G.
AU - De Rycker, Manu
AU - Ajakane, Myriam
AU - Albrecht, Sébastian
AU - Álvarez-Pedraglio, Ana Isabel
AU - Boesche, Markus
AU - Brand, Stephen
AU - Campbell, Lorna
AU - Cantizani-Perez, Juan
AU - Cleghorn, Laura A. T.
AU - Copley, Royston C. B.
AU - Crouch, Sabrinia D.
AU - Daugan, Alain
AU - Drewes, Gerard
AU - Ferrer, Santiago
AU - Ghidelli-Disse, Sonja
AU - Gonzalez, Silvia
AU - Gresham, Stephanie L.
AU - Hill, Alan P.
AU - Hindley, Sean J.
AU - Lowe, Rhiannon M.
AU - MacKenzie, Claire J.
AU - MacLean, Lorna
AU - Manthri, Sujatha
AU - Martin, Franck
AU - Miguel-Siles, Juan
AU - Nguyen, Van Loc
AU - Norval, Suzanne
AU - Osuna-Cabello, Maria
AU - Woodland, Andrew
AU - Patterson, Stephen
AU - Pena, Imanol
AU - Quesada-Campos, Maria Teresa
AU - Reid, Iain H.
AU - Revill, Charlotte
AU - Riley, Jennifer
AU - Ruiz-Gomez, Jose Ramon
AU - Shishikura, Yoko
AU - Simeons, Frederick R. C.
AU - Smith, Alasdair
AU - Smith, Victoria C.
AU - Spinks, Daniel
AU - Stojanovski, Laste
AU - Thomas, John
AU - Thompson, Stephen
AU - Underwood, Tim
AU - Gray, David W.
AU - Fiandor, Jose M.
AU - Gilbert, Ian H.
AU - Wyatt, Paul G.
AU - Read, Kevin D.
AU - Miles, Timothy J.
N1 - Funding: Wellcome trust (nos. 092340 and 100476).
PY - 2019/2/14
Y1 - 2019/2/14
N2 - 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.
AB - 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.
KW - Leishmaniasis
KW - visceral leishmaniasis
KW - anti-visceral leishmaniasis agents
KW - Cdc2-related kinase 12 (CRK12) inhibitor
KW - neglected diseases
UR - http://www.scopus.com/inward/record.url?scp=85059362983&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01218
DO - 10.1021/acs.jmedchem.8b01218
M3 - Article
VL - 62
SP - 1180
EP - 1202
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -