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Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)

[Image: see text] A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds wit...

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Autores principales: Chapman, Timothy M., Osborne, Simon A., Wallace, Claire, Birchall, Kristian, Bouloc, Nathalie, Jones, Hayley M., Ansell, Keith H., Taylor, Debra L., Clough, Barbara, Green, Judith L., Holder, Anthony A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024065/
https://www.ncbi.nlm.nih.gov/pubmed/24689770
http://dx.doi.org/10.1021/jm500342d
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author Chapman, Timothy M.
Osborne, Simon A.
Wallace, Claire
Birchall, Kristian
Bouloc, Nathalie
Jones, Hayley M.
Ansell, Keith H.
Taylor, Debra L.
Clough, Barbara
Green, Judith L.
Holder, Anthony A.
author_facet Chapman, Timothy M.
Osborne, Simon A.
Wallace, Claire
Birchall, Kristian
Bouloc, Nathalie
Jones, Hayley M.
Ansell, Keith H.
Taylor, Debra L.
Clough, Barbara
Green, Judith L.
Holder, Anthony A.
author_sort Chapman, Timothy M.
collection PubMed
description [Image: see text] A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC(50) values less than 10 nM and in vitroP. falciparum antiparasite EC(50) values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.
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spelling pubmed-40240652014-05-19 Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1) Chapman, Timothy M. Osborne, Simon A. Wallace, Claire Birchall, Kristian Bouloc, Nathalie Jones, Hayley M. Ansell, Keith H. Taylor, Debra L. Clough, Barbara Green, Judith L. Holder, Anthony A. J Med Chem [Image: see text] A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC(50) values less than 10 nM and in vitroP. falciparum antiparasite EC(50) values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1. American Chemical Society 2014-04-01 2014-04-24 /pmc/articles/PMC4024065/ /pubmed/24689770 http://dx.doi.org/10.1021/jm500342d Text en Copyright © 2014 American Chemical Society Terms of Use CC-BY (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html)
spellingShingle Chapman, Timothy M.
Osborne, Simon A.
Wallace, Claire
Birchall, Kristian
Bouloc, Nathalie
Jones, Hayley M.
Ansell, Keith H.
Taylor, Debra L.
Clough, Barbara
Green, Judith L.
Holder, Anthony A.
Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)
title Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)
title_full Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)
title_fullStr Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)
title_full_unstemmed Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)
title_short Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)
title_sort optimization of an imidazopyridazine series of inhibitors of plasmodium falciparum calcium-dependent protein kinase 1 (pfcdpk1)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024065/
https://www.ncbi.nlm.nih.gov/pubmed/24689770
http://dx.doi.org/10.1021/jm500342d
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