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合作虚拟筛选鉴定出具有抗 感染模型疗效的 2-芳基-4-氨基喹唑啉系列。

Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an Model of Infection.

机构信息

Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chrome, Fujisawa, Kanagawa 251-8555, Japan.

Celgene Corporation, Celgene Global Health, 10300 Campus Point Drive, San Diego, California 92121, United States.

出版信息

J Med Chem. 2023 Jan 26;66(2):1221-1238. doi: 10.1021/acs.jmedchem.2c00775. Epub 2023 Jan 6.

DOI:10.1021/acs.jmedchem.2c00775
PMID:36607408
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9884087/
Abstract

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against , the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds and , which were profiled further in pharmacokinetic studies and in an model of infection. Compound demonstrated clear reduction of parasitemia in the setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.

摘要

通过虚拟筛选同时探测多个专利药物库，可快速扩展对中度有效化合物的结构-活性关系（SAR），这些化合物针对引起恰加斯病的病原体 。通过基于表型虚拟筛选结果的设计来进行的药效团跃迁，提高了化合物的活性，鉴定了两个有前景的苗头化合物 和 ，它们在药代动力学研究和 感染模型中进一步进行了研究。化合物 在 模型中显示出明显的寄生虫减少，证实了 2-(吡啶-2-基)喹唑啉类化合物作为潜在抗锥虫药物的系列研究具有意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/ab60771211d5/jm2c00775_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/49cb032d2977/jm2c00775_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/8650adf41f9c/jm2c00775_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/03569a577c4c/jm2c00775_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/665f45b94f18/jm2c00775_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/c08e0f0fd576/jm2c00775_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/e8bae5e43b13/jm2c00775_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/c513ab630b48/jm2c00775_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/ab60771211d5/jm2c00775_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/49cb032d2977/jm2c00775_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/8650adf41f9c/jm2c00775_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/03569a577c4c/jm2c00775_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/665f45b94f18/jm2c00775_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/c08e0f0fd576/jm2c00775_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/e8bae5e43b13/jm2c00775_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/c513ab630b48/jm2c00775_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d865/9884087/ab60771211d5/jm2c00775_0006.jpg

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