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Title: A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

Abstract

The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

Authors:
 [1];  [2];  [3];  [1];  [3];  [1];  [4];  [1];  [5];  [5];  [6];  [7];  [8];  [6];  [2];  [2];  [2];  [9];  [9];  [9] more »;  [9];  [9];  [3];  [10];  [11];  [11];  [12];  [12];  [12];  [12];  [12];  [12];  [12];  [12];  [3];  [2] « less
+ Show Author Affiliations
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. Monash Univ., Melbourne, VIC (Australia)
  3. Univ. of Washington, Seattle, WA (United States). Dept. of Chemistry
  4. AbbVie Inc., North Chicago, IL (United States)
  5. Syngene International Ltd., Bangalore (India)
  6. Charles Darwin Univ., Casuarina, NT (Australia)
  7. Eijkman Inst. for Molecular Biology, Jakarta (Indonesia)
  8. Charles Darwin Univ., Casuarina, NT (Australia); Univ. of Oxford (United Kingdom)
  9. GlaxoSmithKline, Madrid (Spain)
  10. Centre Suisse de Recherches Scientifiques en Côte d’Ivoire (Ivory Coast)
  11. Biomedical Primate Research Centre, Rijswijk (The Netherlands)
  12. Medicines for Malaria Venture, Geneva (Switzerland)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1335991
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
ACS Infectious Diseases
Additional Journal Information:
Journal Volume: 2; Journal Issue: 12; Journal ID: ISSN 2373-8227
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; malaria; Plasmodium; pyrimidine biosynthesis; dihydroorotate dehydrogenase

Citation Formats

Phillips, Margaret A., White, Karen L., Kokkonda, Sreekanth, Deng, Xiaoyi, White, John, El Mazouni, Farah, Marsh, Kennan, Tomchick, Diana R., Manjalanagara, Krishne, Rudra, Kakali Rani, Wirjanata, Grennady, Noviyanti, Rintis, Price, Ric N., Marfurt, Jutta, Shackleford, David M., Chiu, Francis C. K., Campbell, Michael, Jimenez-Diaz, Maria Belen, Bazaga, Santiago Ferrer, Angulo-Barturen, Iñigo, Martinez, Maria Santos, Lafuente-Monasterio, Maria, Kaminsky, Werner, Silue, Kigbafori, Zeeman, Anne-Marie, Kocken, Clemens, Leroy, Didier, Blasco, Benjamin, Rossignol, Emilie, Rueckle, Thomas, Matthews, Dave, Burrows, Jeremy N., Waterson, David, Palmer, Michael J., Rathod, Pradipsinh K., and Charman, Susan A. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria. United States: N. p., 2016. Web. doi:10.1021/acsinfecdis.6b00144.
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Phillips, Margaret A., White, Karen L., Kokkonda, Sreekanth, Deng, Xiaoyi, White, John, El Mazouni, Farah, Marsh, Kennan, Tomchick, Diana R., Manjalanagara, Krishne, Rudra, Kakali Rani, Wirjanata, Grennady, Noviyanti, Rintis, Price, Ric N., Marfurt, Jutta, Shackleford, David M., Chiu, Francis C. K., Campbell, Michael, Jimenez-Diaz, Maria Belen, Bazaga, Santiago Ferrer, Angulo-Barturen, Iñigo, Martinez, Maria Santos, Lafuente-Monasterio, Maria, Kaminsky, Werner, Silue, Kigbafori, Zeeman, Anne-Marie, Kocken, Clemens, Leroy, Didier, Blasco, Benjamin, Rossignol, Emilie, Rueckle, Thomas, Matthews, Dave, Burrows, Jeremy N., Waterson, David, Palmer, Michael J., Rathod, Pradipsinh K., & Charman, Susan A. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria. United States. https://doi.org/10.1021/acsinfecdis.6b00144
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Phillips, Margaret A., White, Karen L., Kokkonda, Sreekanth, Deng, Xiaoyi, White, John, El Mazouni, Farah, Marsh, Kennan, Tomchick, Diana R., Manjalanagara, Krishne, Rudra, Kakali Rani, Wirjanata, Grennady, Noviyanti, Rintis, Price, Ric N., Marfurt, Jutta, Shackleford, David M., Chiu, Francis C. K., Campbell, Michael, Jimenez-Diaz, Maria Belen, Bazaga, Santiago Ferrer, Angulo-Barturen, Iñigo, Martinez, Maria Santos, Lafuente-Monasterio, Maria, Kaminsky, Werner, Silue, Kigbafori, Zeeman, Anne-Marie, Kocken, Clemens, Leroy, Didier, Blasco, Benjamin, Rossignol, Emilie, Rueckle, Thomas, Matthews, Dave, Burrows, Jeremy N., Waterson, David, Palmer, Michael J., Rathod, Pradipsinh K., and Charman, Susan A. Tue . "A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria". United States. https://doi.org/10.1021/acsinfecdis.6b00144. https://www.osti.gov/servlets/purl/1335991.
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@article{osti_1335991,
title = {A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria},
author = {Phillips, Margaret A. and White, Karen L. and Kokkonda, Sreekanth and Deng, Xiaoyi and White, John and El Mazouni, Farah and Marsh, Kennan and Tomchick, Diana R. and Manjalanagara, Krishne and Rudra, Kakali Rani and Wirjanata, Grennady and Noviyanti, Rintis and Price, Ric N. and Marfurt, Jutta and Shackleford, David M. and Chiu, Francis C. K. and Campbell, Michael and Jimenez-Diaz, Maria Belen and Bazaga, Santiago Ferrer and Angulo-Barturen, Iñigo and Martinez, Maria Santos and Lafuente-Monasterio, Maria and Kaminsky, Werner and Silue, Kigbafori and Zeeman, Anne-Marie and Kocken, Clemens and Leroy, Didier and Blasco, Benjamin and Rossignol, Emilie and Rueckle, Thomas and Matthews, Dave and Burrows, Jeremy N. and Waterson, David and Palmer, Michael J. and Rathod, Pradipsinh K. and Charman, Susan A.},
abstractNote = {The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.},
doi = {10.1021/acsinfecdis.6b00144},
journal = {ACS Infectious Diseases},
number = 12,
volume = 2,
place = {United States},
year = {Tue Oct 04 00:00:00 EDT 2016},
month = {Tue Oct 04 00:00:00 EDT 2016}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1021/acsinfecdis.6b00144
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Cited by: 63 works
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Figures / Tables:

Table 1 Table 1: SAR of select compounds from the triazolopyrimidine series
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    Works referencing / citing this record:

    The resistome and genomic reconnaissance in the age of malaria elimination
    journal, December 2019

    • Kümpornsin, Krittikorn; Kochakarn, Theerarat; Chookajorn, Thanat
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    • Antimicrobial Agents and Chemotherapy, Vol. 62, Issue 9
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    Chemical structure modifications and nano-technology applications for improving ADME-Tox properties, a review
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    • Phillips, Margaret A.; Burrows, Jeremy N.; Manyando, Christine
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    An in vitro toolbox to accelerate anti-malarial drug discovery and development
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    The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines
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    • Kümpornsin, Krittikorn; Kochakarn, Theerarat; Chookajorn, Thanat
    • Disease Models & Mechanisms, Vol. 12, Issue 12
    • DOI: 10.1242/dmm.040717

    The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines
    journal, November 2019

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      Figure 4 (p. 49)figure
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