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

被引：11
|
作者：
Large, Jonathan M. [1 ]
Birchall, Kristian [1 ]
Bouloc, Nathalie S. [1 ]
Merritt, Andy T. [1 ]
Smiljanic-Hurley, Ela [1 ]
Tsagris, Denise J. [1 ]
Wheldon, Mary C. [1 ]
Ansell, Keith H. [1 ]
Coombs, Peter J. [1 ]
Kettleborough, Catherine A. [1 ]
Whalley, David [1 ]
Stewart, Lindsay B. [2 ]
Bowyer, Paul W. [2 ]
Baker, David A. [2 ]
Osborne, Simon A. [1 ]
机构：
[1] LifeArc, Ctr Therapeut Discovery, Accelerator Bldg,Open Innovat Campus, Stevenage SG1 2FX, Herts, England
[2] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Keppel St, London WC1E 7HT, England
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 19期
关键词：
Malaria; Plasmodium falciparum; cGMP; Protein kinase G; Imidazopyridine; SAR; IMIDAZOPYRIDAZINES;
D O I：
10.1016/j.bmcl.2019.08.014
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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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页数：6
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