鉴定吲唑和氮杂吲唑取代的环戊并吡咯作为治疗中枢神经系统疾病的G2019S富亮氨酸重复激酶2抑制剂
Identification of Indazole- and Azaindazole-Substituted Cyclopentapyrroles as G2019S Leucine-Rich Repeat Kinase 2 Inhibitors for the Treatment of CNS Disorders.
作者信息
Feng Siyan, Liang Steven H
机构信息
Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States.
出版信息
ACS Med Chem Lett. 2025 Feb 13;16(3):368-370. doi: 10.1021/acsmedchemlett.5c00045. eCollection 2025 Mar 13.
Abstract
This patent describes a novel class of novel indazole/azaindazole-substituted cyclopentapyrroles, which selectively inhibit the Leucine-Rich Repeat Kinase 2 (LRRK2) with G2019S mutation. These LRRK2 inhibitors are proposed for treating Parkinson's diseases, Alzheimer's disease, and other central nervous system (CNS) disorders.
摘要
该专利描述了一类新型的吲唑/氮杂吲唑取代的环戊并吡咯，其可选择性抑制具有G2019S突变的富含亮氨酸重复激酶2（LRRK2）。这些LRRK2抑制剂被提议用于治疗帕金森病、阿尔茨海默病及其他中枢神经系统（CNS）疾病。
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J Med Chem. 2024 Feb 22;67(4):2559-2569. doi: 10.1021/acs.jmedchem.3c01687. Epub 2024 Feb 2.
2
Small-molecule LRRK2 inhibitors for PD therapy: Current achievements and future perspectives.小分子 LRRK2 抑制剂治疗 PD：当前成就与未来展望。
Eur J Med Chem. 2023 Aug 5;256:115475. doi: 10.1016/j.ejmech.2023.115475. Epub 2023 May 10.
3
Imaging Leucine-Rich Repeat Kinase 2 In Vivo with F-Labeled Positron Emission Tomography Ligand.利用 F 标记的正电子发射断层扫描配体在体内成像富含亮氨酸重复激酶 2。
J Med Chem. 2023 Feb 9;66(3):1712-1724. doi: 10.1021/acs.jmedchem.2c00551. Epub 2022 Oct 18.
4
LRRK2 and idiopathic Parkinson's disease.LRRK2 与特发性帕金森病。
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