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;
+5 more...Whalley, David;
Stewart, Lindsay B;
Bowyer, Paul W;
Baker, David A;
Osborne, Simon A;
(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: https://doi.org/10.1016/j.bmcl.2019.08.014
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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.