5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy

Ding, Xiao; Stasi, Luigi; Dai, Xuezhi; Long, Kai; Peng, Cheng; Zhao, Baowei; Wang, Hailong; Sun, Changhui; Huan, Hu; Wan, Zhimin; Jandu, Karamjit S.; Philps, Oliver; Chen, Yan; Wang, Lizhen; Liu, Qian; Edge, C.; Li, Yang; Dong, Kelly; Guan, Xiao-Ming; Tattersall, F.D.; Reith, Alastair D.; Ren, Feng

doi:10.1016/j.bmcl.2018.11.054

Cited by 13 publications

(5 citation statements)

References 20 publications

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“…Ding et al reported the development of 5-substituted- N -pyridazinylbenzamide LRRK2 inhibitors . The lead compound 1 exhibited high potency and selectivity toward LRRK2 (Figure A) .…”

Section: Lrrk2 Inhibitorsmentioning

confidence: 99%

“…Ding et al reported the development of 5-substituted-N-pyridazinylbenzamide LRRK2 inhibitors. 137 The lead compound 1 exhibited high potency and selectivity toward LRRK2 (Figure 5A). 138 However, despite its high exposure in the brain, no considerable decrease in LRRK2 phosphorylation at Ser935 was detected, indicating a lack of target involvement in the central nervous system (CNS).…”

Section: Recently Disclosed Lrrk2 Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Ding et al reported the development of 5-substituted- N -pyridazinylbenzamide LRRK2 inhibitors . The lead compound 1 exhibited high potency and selectivity toward LRRK2 (Figure A) .…”

Section: Lrrk2 Inhibitorsmentioning

confidence: 99%

Section: Recently Disclosed 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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“…Recently, first-generation 'tool' inhibitors that exhibit excellent potency and selectivity for LRRK2 such as LRRK2-IN-1 [31], GSK2578215A [32], TAE684 and CZC-251469 [33] have been reported with nanaomolar range, but incapable of crossing the blood brain barrier. Soon after, HG-10-102-01 [34], GNE-7915 [35], JH-II-127 [36], PF-06447475 [37], MLi-2 [38], 5-substituted-N-pyridazinylbenzamide derivatives [39] and 5-azaindazole inhibitors [40] are reposted as selective and brain penetrant LRRK2 kinase inhibitors.…”

Section: Lrrk2 As a Therapeutic Targetmentioning

confidence: 99%

LRRK2 Signalling Pathways in Parkinson’s Disease

Zhang

2019

ANN

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“…Nonetheless, structurally diverse inhibitors of LRRK2 have been identified over the past decade. A great deal of scientific endeavors have led to the discovery of novel potent inhibitors involving aminoquinazoline [ 13 ], pyrazole biaryl sulfonamide [ 14 ], pyrrolo [2,3-d]pyrimidine [ 15 ], constrained peptide [ 16 ], proteolysis targeting chimera [ 17 ], benzothiazole [ 18 ], azaindazole [ 19 , 20 ], 4,7-dihydrotetrazolo [1,5- a ]pyrimidine [ 21 ], N-pyridazinylbenzamide [ 22 ], 4-ethoxy-7H-pyrrolo [2,3- d ]pyrimidin-2-amine [ 23 ], 3-(4-pyrimidinyl) indazole [ 24 ], 2-aminopyridine [ 25 ], indolinone [ 26 ], triazolopyridazine [ 27 ], and 2-anilino-4-methylamino-5-chloropyrimidine [ 28 ] as the key structural elements. Although the majority of LRRK2 inhibitors have been identified through the screening of a chemical library or chemical derivatizations of the known inhibitor scaffolds, several rational drug design methods have also been applied using various molecular modeling techniques [ 29 , 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2

Park

Kim

et al. 2022

IJMS

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Missense mutations of leucine-rich repeat kinase 2 (LRRK2), including the G2019S mutant, are responsible for the pathogenesis of Parkinson’s disease. In this work, structure-based virtual screening of a large chemical library was carried out to identify a number of novel inhibitors of the G2019S mutant of LRRK2, the biochemical potencies of which ranged from the low micromolar to the submicromolar level. The discovery of these potent inhibitors was made possible due to the modification of the original protein–ligand binding energy function in order to include an accurate ligand dehydration energy term. The results of extensive molecular docking simulations indicated that the newly identified inhibitors were bound to the ATP-binding site of the G2019S mutant of LRRK2 through the multiple hydrogen bonds with backbone amide groups in the hinge region as well as the hydrophobic interactions with the nonpolar residues in the P-loop, hinge region, and interdomain region. Among 18 inhibitors derived from virtual screening, 4-(2-amino-5-phenylpyrimidin-4-yl)benzene-1,3-diol (Inhibitor 2) is most likely to serve as a new molecular scaffold to optimize the biochemical potency, because it revealed submicromolar inhibitory activity in spite of its low molecular weight (279.3 amu). Indeed, a highly potent inhibitor (Inhibitor 2n) of the G2019S mutant was derived via the structure-based de novo design using the structure of Inhibitor 2 as the molecular core. The biochemical potency of Inhibitor 2n surged to the nanomolar level due to the strengthening of hydrophobic interactions in the ATP-binding site, which were presumably caused by the substitutions of small nonpolar moieties. Due to the high biochemical potency against the G2019S mutant of LRRK2 and the putatively good physicochemical properties, Inhibitor 2n is anticipated to serve as a new lead compound for the discovery of antiparkinsonian medicines.

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5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy

Cited by 13 publications

References 20 publications

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

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

LRRK2 Signalling Pathways in Parkinson’s Disease

Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2

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