Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors

Ding, Xiao; Stasi, Luigi; Ho, Ming‐Hsun; Zhao, Baowei; Wang, Hailong; Long, Kai; Xu, Qiongfeng; Sang, Yingxia; Sun, Changhui; Hu, Huan; Yu, Haihua; Wan, Zhimin; Wang, Lizhen; Edge, C.; Liu, Qian; Li, Yang; Dong, Kelly; Guan, Xiao-Ming; Tattersall, F.D.; Reith, Alastair D.; Ren, Feng

doi:10.1016/j.bmcl.2018.03.045

Cited by 17 publications

(7 citation statements)

References 24 publications

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“…Compound 7 (LRRK2 inhibitor 1) was discovered in a series of 7H-pyrrolo [2,3-d] pyrimidin-2-amine derivatives. In an homogeneous time-resolved fluorescence (HTRF) assay Compound 7 displayed an IC 50 against LRRK2 of 6.8 nM [ 127 ]. Compound 7 ’s kinase selectivity was investigated utilizing the HotSpot test platform comprising over 340 more kinases.…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

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Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

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Section: Kinase Inhibitorsmentioning

confidence: 99%

“…Compound 7 inhibited CYP3A4 significantly but had a lesser affinity for hERG. The authors concluded that further optimization of this series toward a clinical candidate would be published in due time [ 127 ].…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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“…Because the aberrant kinase activity of LRRK2 is associated with disease pathogenesis, most efforts in drug discovery have been focused on inhibiting its kinase domain. This has yielded a number of highly specific and potential inhibitors of LRRK2 kinase activity [92,93,94]. However, inhibition of LRRK2 kinase activity has led to detrimental side-effects in animal models [37,38,95,96].…”

Section: Discussionmentioning

confidence: 99%

Roco Proteins and the Parkinson’s Disease-Associated LRRK2

Liao

Hoang

2018

IJMS

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Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes.

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“…A series of 4-ethoxy-7 H -pyrrolo[2,3- d ]pyrimidin-2-amine derivatives was identified by Ding et al through a kinase-focused set screening. The hit compound 19 (Figure A) exhibited good LRRK2 inhibitory potency but poor solubility, permeability, and selectivity due to its high TPSA and five HBDs.…”

Section: Lrrk2 Inhibitorsmentioning

confidence: 99%

The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease

Xing

et al. 2023

J. Med. Chem.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in idiopathic and familial PD cases. LRRK2 mutations are involved in multiple PD pathogeneses, including dysregulation of mitochondrial homeostasis, ciliogenesis, etc. Here, we provide a comprehensive overview of the biological function, structure, and mutations of LRRK2. We also examine recent advances and challenges in developing LRRK2 inhibitors and address prospective protein-based targeting strategies. The binding mechanisms, structure−activity relationships, and pharmacokinetic features of inhibitors are emphasized to provide a comprehensive compendium on the rational design of LRRK2 inhibitors. We hope that this publication can serve as a guide for designing novel LRRK2 inhibitors based on the summarized facts and perspectives.

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Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors

Cited by 17 publications

References 24 publications

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Roco Proteins and the Parkinson’s Disease-Associated LRRK2

The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease

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