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强效双环疟疾cGMP依赖性蛋白激酶抑制剂：结合提高细胞效力、选择性和结构新颖性的方法

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

作者信息

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, Whalley David, Stewart Lindsay B, Bowyer Paul W, Baker David A, Osborne Simon A

机构信息

Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, UK.

Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, UK.

出版信息

Bioorg Med Chem Lett. 2019 Oct 1;29(19):126610. doi: 10.1016/j.bmcl.2019.08.014. Epub 2019 Aug 9.

DOI:10.1016/j.bmcl.2019.08.014
PMID:31471167
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6857626/
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.

摘要

针对恶性疟原虫环磷酸鸟苷依赖性蛋白激酶（PfPKG）的咪唑并吡啶抑制剂的重点研究已使该系列在体外特性方面取得了显著进展。本文描述了基于配体效率（LLE）的方法，用于结合细胞活性、关键物理化学参数和结构新颖性方面的改进，并且一个与取代基区域化学相关的基于结构的设计假设已指导针对具有平衡活性、药物代谢动力学（ADME）和激酶选择性特征的关键实例展开研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/892e7628711e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/edbf7ca01068/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/bf6448461836/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/aefabd0dab13/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/04a1cbcfbe78/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/9f27c2c49546/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/a9996e7b4770/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/f13489963c19/fx6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/90ab9e1ada5e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/621857f59c9b/fx7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/8080615069a9/fx11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/892e7628711e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/edbf7ca01068/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/bf6448461836/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/aefabd0dab13/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/04a1cbcfbe78/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/9f27c2c49546/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/a9996e7b4770/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/f13489963c19/fx6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/90ab9e1ada5e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/621857f59c9b/fx7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/8080615069a9/fx11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab3c/6857626/892e7628711e/gr3.jpg

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本文引用的文献

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Bioorg Med Chem Lett. 2019 Feb 1;29(3):509-514. doi: 10.1016/j.bmcl.2018.11.039. Epub 2018 Nov 20.
2
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Bioorg Med Chem Lett. 2018 Oct 15;28(19):3168-3173. doi: 10.1016/j.bmcl.2018.08.028. Epub 2018 Aug 27.
3
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The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance.恶性疟原虫ABC转运蛋白ABCI3赋予寄生虫株依赖性多效抗疟药物抗性。
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