Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate

M. A. Phillips; P. K. Rathod; T. Rueckle; D. Matthews; J. N. Burrows; S. A. Charman

doi:10.1016/B978-0-12-409547-2.12470-9

Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate

M. A. Phillips, P. K. Rathod, T. Rueckle, D. Matthews, J. N. Burrows, S. A. Charman

Centre for Drug Candidate Optimisation

Research output: Chapter in Book/Report/Conference proceeding › Chapter (Book) › Other › peer-review

8 Citations (Scopus)

Abstract

Half of the globe remains at risk for malaria, yet drug resistance threatens current treatments. DSM265 was discovered through a target-based screen and subsequent structure-guided lead optimization, as a novel triazolopyrimidine-based inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH). DSM265 is the first antimalarial targeting DHODH and, due to its novel mechanism, is expected to function against Plasmodium species resistant to current chemotherapies. Key DSM265 characteristics include blood- and liver-stage activity, parasite selectivity, and a long human half-life, supporting its development as either a single dose treatment or once weekly prophylactic, in combination with a suitable partner to help prevent resistance.

Original language	English
Title of host publication	Comprehensive Medicinal Chemistry III
Subtitle of host publication	Case Histories in Recent Drug Discovery
Editors	Samuel Chackalamannil, David Rotella, Simon E Ward
Place of Publication	Amsterdam The Netherlands
Publisher	Elsevier
Chapter	8.22
Pages	544-557
Number of pages	14
Volume	8
Edition	3
ISBN (Electronic)	9780128032008
ISBN (Print)	9780128032015
DOIs	https://doi.org/10.1016/B978-0-12-409547-2.12470-9
Publication status	Published - 3 Jun 2017

Publication series

Name	Reference Module in Chemistry, Molecular Sciences and Chemical Engineering
Publisher	Elsevier
Number	3
Volume	8

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Artemisinin.
DHODH.
Dihydroorotate dehydrogenase.
DSM265.
Malaria.
Plasmodium.
Pyrimidine.
Triazolopyrimidine

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10.1016/B978-0-12-409547-2.12470-9

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Phillips, M. A., Rathod, P. K., Rueckle, T., Matthews, D., Burrows, J. N., & Charman, S. A. (2017). Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate. In S. Chackalamannil, D. Rotella, & S. E. Ward (Eds.), Comprehensive Medicinal Chemistry III: Case Histories in Recent Drug Discovery (3 ed., Vol. 8, pp. 544-557). (Reference Module in Chemistry, Molecular Sciences and Chemical Engineering; Vol. 8, No. 3). Elsevier. https://doi.org/10.1016/B978-0-12-409547-2.12470-9

Phillips, M. A. ; Rathod, P. K. ; Rueckle, T. et al. / Medicinal Chemistry Case History : Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate. Comprehensive Medicinal Chemistry III: Case Histories in Recent Drug Discovery. editor / Samuel Chackalamannil ; David Rotella ; Simon E Ward. Vol. 8 3. ed. Amsterdam The Netherlands : Elsevier, 2017. pp. 544-557 (Reference Module in Chemistry, Molecular Sciences and Chemical Engineering; 3).

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title = "Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate",

abstract = "Half of the globe remains at risk for malaria, yet drug resistance threatens current treatments. DSM265 was discovered through a target-based screen and subsequent structure-guided lead optimization, as a novel triazolopyrimidine-based inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH). DSM265 is the first antimalarial targeting DHODH and, due to its novel mechanism, is expected to function against Plasmodium species resistant to current chemotherapies. Key DSM265 characteristics include blood- and liver-stage activity, parasite selectivity, and a long human half-life, supporting its development as either a single dose treatment or once weekly prophylactic, in combination with a suitable partner to help prevent resistance.",

keywords = "Artemisinin., DHODH., Dihydroorotate dehydrogenase., DSM265., Malaria., Plasmodium., Pyrimidine., Triazolopyrimidine",

author = "Phillips, \{M. A.\} and Rathod, \{P. K.\} and T. Rueckle and D. Matthews and Burrows, \{J. N.\} and Charman, \{S. A.\}",

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Phillips, MA, Rathod, PK, Rueckle, T, Matthews, D, Burrows, JN & Charman, SA 2017, Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate. in S Chackalamannil, D Rotella & SE Ward (eds), Comprehensive Medicinal Chemistry III: Case Histories in Recent Drug Discovery. 3 edn, vol. 8, Reference Module in Chemistry, Molecular Sciences and Chemical Engineering, no. 3, vol. 8, Elsevier, Amsterdam The Netherlands, pp. 544-557. https://doi.org/10.1016/B978-0-12-409547-2.12470-9

Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate. / Phillips, M. A.; Rathod, P. K.; Rueckle, T. et al.
Comprehensive Medicinal Chemistry III: Case Histories in Recent Drug Discovery. ed. / Samuel Chackalamannil; David Rotella; Simon E Ward. Vol. 8 3. ed. Amsterdam The Netherlands: Elsevier, 2017. p. 544-557 (Reference Module in Chemistry, Molecular Sciences and Chemical Engineering; Vol. 8, No. 3).

Research output: Chapter in Book/Report/Conference proceeding › Chapter (Book) › Other › peer-review

TY - CHAP

T1 - Medicinal Chemistry Case History

T2 - Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate

AU - Phillips, M. A.

AU - Rathod, P. K.

AU - Rueckle, T.

AU - Matthews, D.

AU - Burrows, J. N.

AU - Charman, S. A.

PY - 2017/6/3

Y1 - 2017/6/3

N2 - Half of the globe remains at risk for malaria, yet drug resistance threatens current treatments. DSM265 was discovered through a target-based screen and subsequent structure-guided lead optimization, as a novel triazolopyrimidine-based inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH). DSM265 is the first antimalarial targeting DHODH and, due to its novel mechanism, is expected to function against Plasmodium species resistant to current chemotherapies. Key DSM265 characteristics include blood- and liver-stage activity, parasite selectivity, and a long human half-life, supporting its development as either a single dose treatment or once weekly prophylactic, in combination with a suitable partner to help prevent resistance.

AB - Half of the globe remains at risk for malaria, yet drug resistance threatens current treatments. DSM265 was discovered through a target-based screen and subsequent structure-guided lead optimization, as a novel triazolopyrimidine-based inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH). DSM265 is the first antimalarial targeting DHODH and, due to its novel mechanism, is expected to function against Plasmodium species resistant to current chemotherapies. Key DSM265 characteristics include blood- and liver-stage activity, parasite selectivity, and a long human half-life, supporting its development as either a single dose treatment or once weekly prophylactic, in combination with a suitable partner to help prevent resistance.

KW - Artemisinin.

KW - DHODH.

KW - Dihydroorotate dehydrogenase.

KW - DSM265.

KW - Malaria.

KW - Plasmodium.

KW - Pyrimidine.

KW - Triazolopyrimidine

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U2 - 10.1016/B978-0-12-409547-2.12470-9

DO - 10.1016/B978-0-12-409547-2.12470-9

M3 - Chapter (Book)

AN - SCOPUS:85040428304

SN - 9780128032015

VL - 8

T3 - Reference Module in Chemistry, Molecular Sciences and Chemical Engineering

SP - 544

EP - 557

BT - Comprehensive Medicinal Chemistry III

A2 - Chackalamannil, Samuel

A2 - Rotella, David

A2 - Ward, Simon E

PB - Elsevier

CY - Amsterdam The Netherlands

ER -

Phillips MA, Rathod PK, Rueckle T, Matthews D, Burrows JN, Charman SA. Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate. In Chackalamannil S, Rotella D, Ward SE, editors, Comprehensive Medicinal Chemistry III: Case Histories in Recent Drug Discovery. 3 ed. Vol. 8. Amsterdam The Netherlands: Elsevier. 2017. p. 544-557. (Reference Module in Chemistry, Molecular Sciences and Chemical Engineering; 3). doi: 10.1016/B978-0-12-409547-2.12470-9

Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate

Abstract

Publication series

UN SDGs

Keywords

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