dc.contributor.author |
Brunschwig, C
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dc.contributor.author |
Lawrence, N
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dc.contributor.author |
Taylor, D
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dc.contributor.author |
Abay, E
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dc.contributor.author |
Njoroge, M
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dc.contributor.author |
Basarab, GS
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dc.contributor.author |
Le Manach, C
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dc.contributor.author |
Paquet, T
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dc.contributor.author |
Cabrera, DG
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dc.contributor.author |
Mancama, Dalubuhle T
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|
dc.date.accessioned |
2018-12-11T08:50:47Z |
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dc.date.available |
2018-12-11T08:50:47Z |
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dc.date.issued |
2018-09 |
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dc.identifier.citation |
Brunschwig, C. et al. 2018. UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria. Antimicrobial Agents and Chemotherapy: DOI: 10.1128/AAC.00012-18 |
en_US |
dc.identifier.issn |
0066-4804 |
|
dc.identifier.issn |
1098-6596 |
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dc.identifier.uri |
https://aac.asm.org/content/62/9/e00012-18
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dc.identifier.uri |
doi: 10.1128/AAC.00012-18
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|
dc.identifier.uri |
https://www.ncbi.nlm.nih.gov/pubmed/29941635
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|
dc.identifier.uri |
http://hdl.handle.net/10204/10585
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|
dc.description.abstract |
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2R null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria. |
en_US |
dc.description.sponsorship |
Copyright: 2018 American Society for Microbiology. Due to copyright restrictions, the attached PDF file only contains the abstract of the full text item. For access to the full text item, please consult the publisher's website. |
en_US |
dc.language.iso |
en |
en_US |
dc.publisher |
American Society for Microbiology |
en_US |
dc.relation.ispartofseries |
Worklist;21563 |
|
dc.subject |
1-phosphatidylinositol 4-kinase inhibitor |
en_US |
dc.subject |
Absorption |
en_US |
dc.subject |
Distribution metabolism |
en_US |
dc.subject |
Drug discovery |
en_US |
dc.subject |
Excretion |
en_US |
dc.subject |
Human dose prediction |
en_US |
dc.subject |
In vivo efficacy |
en_US |
dc.subject |
Malaria |
en_US |
dc.subject |
Pharmacokinetic/pharmacodynamic modeling |
en_US |
dc.subject |
Pharmacokinetics |
en_US |
dc.subject |
Plasmodium spp |
en_US |
dc.title |
UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria |
en_US |
dc.type |
Article |
en_US |
dc.identifier.apacitation |
Brunschwig, C., Lawrence, N., Taylor, D., Abay, E., Njoroge, M., Basarab, G., ... Mancama, D. T. (2018). UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria. http://hdl.handle.net/10204/10585 |
en_ZA |
dc.identifier.chicagocitation |
Brunschwig, C, N Lawrence, D Taylor, E Abay, M Njoroge, GS Basarab, C Le Manach, T Paquet, DG Cabrera, and Dalubuhle T Mancama "UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria." (2018) http://hdl.handle.net/10204/10585 |
en_ZA |
dc.identifier.vancouvercitation |
Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab G, et al. UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria. 2018; http://hdl.handle.net/10204/10585. |
en_ZA |
dc.identifier.ris |
TY - Article
AU - Brunschwig, C
AU - Lawrence, N
AU - Taylor, D
AU - Abay, E
AU - Njoroge, M
AU - Basarab, GS
AU - Le Manach, C
AU - Paquet, T
AU - Cabrera, DG
AU - Mancama, Dalubuhle T
AB - The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2R null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.
DA - 2018-09
DB - ResearchSpace
DP - CSIR
KW - 1-phosphatidylinositol 4-kinase inhibitor
KW - Absorption
KW - Distribution metabolism
KW - Drug discovery
KW - Excretion
KW - Human dose prediction
KW - In vivo efficacy
KW - Malaria
KW - Pharmacokinetic/pharmacodynamic modeling
KW - Pharmacokinetics
KW - Plasmodium spp
LK - https://researchspace.csir.co.za
PY - 2018
SM - 0066-4804
SM - 1098-6596
T1 - UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria
TI - UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria
UR - http://hdl.handle.net/10204/10585
ER -
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en_ZA |