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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Detalles Bibliográficos
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
Descripción
Sumario: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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