Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty

Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters an...

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Autores principales: Large, Jonathan M., Birchall, Kristian, Bouloc, Nathalie S., Merritt, Andy T., Smiljanic-Hurley, Ela, Tsagris, Denise J., Wheldon, Mary C., Ansell, Keith H., Coombs, Peter J., Kettleborough, Catherine A., Whalley, David, Stewart, Lindsay B., Bowyer, Paul W., Baker, David A., Osborne, Simon A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857626/
https://www.ncbi.nlm.nih.gov/pubmed/31471167
http://dx.doi.org/10.1016/j.bmcl.2019.08.014
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author Large, Jonathan M.
Birchall, Kristian
Bouloc, Nathalie S.
Merritt, Andy T.
Smiljanic-Hurley, Ela
Tsagris, Denise J.
Wheldon, Mary C.
Ansell, Keith H.
Coombs, Peter J.
Kettleborough, Catherine A.
Whalley, David
Stewart, Lindsay B.
Bowyer, Paul W.
Baker, David A.
Osborne, Simon A.
author_facet Large, Jonathan M.
Birchall, Kristian
Bouloc, Nathalie S.
Merritt, Andy T.
Smiljanic-Hurley, Ela
Tsagris, Denise J.
Wheldon, Mary C.
Ansell, Keith H.
Coombs, Peter J.
Kettleborough, Catherine A.
Whalley, David
Stewart, Lindsay B.
Bowyer, Paul W.
Baker, David A.
Osborne, Simon A.
author_sort Large, Jonathan M.
collection PubMed
description Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters and structural novelty are described, and a structure-based design hypothesis relating to substituent regiochemistry has directed efforts towards key examples with well-balanced potency, ADME and kinase selectivity profiles.
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spelling pubmed-68576262019-11-21 Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty Large, Jonathan M. Birchall, Kristian Bouloc, Nathalie S. Merritt, Andy T. Smiljanic-Hurley, Ela Tsagris, Denise J. Wheldon, Mary C. Ansell, Keith H. Coombs, Peter J. Kettleborough, Catherine A. Whalley, David Stewart, Lindsay B. Bowyer, Paul W. Baker, David A. Osborne, Simon A. Bioorg Med Chem Lett Article Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters and structural novelty are described, and a structure-based design hypothesis relating to substituent regiochemistry has directed efforts towards key examples with well-balanced potency, ADME and kinase selectivity profiles. Elsevier Science Ltd 2019-10-01 /pmc/articles/PMC6857626/ /pubmed/31471167 http://dx.doi.org/10.1016/j.bmcl.2019.08.014 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Large, Jonathan M.
Birchall, Kristian
Bouloc, Nathalie S.
Merritt, Andy T.
Smiljanic-Hurley, Ela
Tsagris, Denise J.
Wheldon, Mary C.
Ansell, Keith H.
Coombs, Peter J.
Kettleborough, Catherine A.
Whalley, David
Stewart, Lindsay B.
Bowyer, Paul W.
Baker, David A.
Osborne, Simon A.
Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty
title Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty
title_full Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty
title_fullStr Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty
title_full_unstemmed Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty
title_short Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty
title_sort potent bicyclic inhibitors of malarial cgmp-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857626/
https://www.ncbi.nlm.nih.gov/pubmed/31471167
http://dx.doi.org/10.1016/j.bmcl.2019.08.014
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