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


ABSTRACT: 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.

SUBMITTER: Large JM 

PROVIDER: S-EPMC6857626 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Large Jonathan M JM   Birchall Kristian K   Bouloc Nathalie S NS   Merritt Andy T AT   Smiljanic-Hurley Ela E   Tsagris Denise J DJ   Wheldon Mary C MC   Ansell Keith H KH   Coombs Peter J PJ   Kettleborough Catherine A CA   Whalley David D   Stewart Lindsay B LB   Bowyer Paul W PW   Baker David A DA   Osborne Simon A SA  

Bioorganic & medicinal chemistry letters 20190809 19


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  ...[more]

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