Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty.
Jonathan M Large;
Kristian Birchall;
Nathalie S Bouloc;
Andy T Merritt;
Ela Smiljanic-Hurley;
Denise J Tsagris;
Mary C Wheldon;
Keith H Ansell;
Peter J Coombs;
Catherine A Kettleborough;
+5 more...
David Whalley;
Lindsay B Stewart;
Paul W Bowyer;
David A Baker 
;
Simon A Osborne;
(2019)
Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty.
Bioorganic & medicinal chemistry letters, 29 (19).
126610-.
ISSN 0960-894X
DOI: 10.1016/j.bmcl.2019.08.014
;
Simon A Osborne;
(2019)
Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty.
Bioorganic & medicinal chemistry letters, 29 (19).
126610-.
ISSN 0960-894X
DOI: 10.1016/j.bmcl.2019.08.014
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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