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
; and 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: 10.1016/j.bmcl.2019.08.014
; and 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: 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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