发现1-吡唑联芳基磺酰胺类化合物作为新型G2019S-LRRK2激酶抑制剂
Discovery of 1Pyrazole Biaryl Sulfonamides as Novel G2019S-LRRK2 Kinase Inhibitors.
作者信息
Leśniak Robert K, Nichols R Jeremy, Schonemann Marcus, Zhao Jing, Gajera Chandresh R, Lam Grace, Nguyen Khanh C, Langston J William, Smith Mark, Montine Thomas J
机构信息
Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States.
Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, California 94305, United States.
出版信息
ACS Med Chem Lett. 2022 May 23;13(6):981-988. doi: 10.1021/acsmedchemlett.2c00116. eCollection 2022 Jun 9.
Abstract
G2019S (GS) is the most prevalent mutation in the leucine rich repeat protein kinase 2 gene (), a genetic predisposition that is common for Parkinson's disease, as well as for some forms of cancer, and is a shared risk allele for Crohn's disease. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted LRRK2 kinase, few have reached clinical development. We report the discovery and preliminary development of an entirely novel structural class of potent and selective GS-LRRK2 kinase inhibitors: biaryl-1-pyrazoles.
摘要
G2019S（GS）是富含亮氨酸重复序列蛋白激酶2基因（）中最常见的突变，这种遗传易感性在帕金森病以及某些癌症类型中很常见，并且是克罗恩病的一个共享风险等位基因。GS-LRRK2具有过度活跃的激酶，尽管众多药物研发项目都以LRRK2激酶为靶点，但很少有进入临床开发阶段的。我们报告了一种全新结构类型的强效且选择性GS-LRRK2激酶抑制剂的发现和初步开发：联芳基-1-吡唑。
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2
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3
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6
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8
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9
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10
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