Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders

Xu, Heng; Lu, Huiqing; Xu, Zhongmiao; Luan, Linbo; Li, Chengyong; Xu, Yan; Dong, Kelly; Li, Xiong; Li, Yvonne; Liu, Gentao; Gong, Sophie; Zhao, Yonggang; Liu, Ailian; Zhang, Yueting; Zhang, Wei; Cai, Xin; Xiang, Jia‐Ning; Elliott, John D.; Lin, Xichen

doi:10.1021/acsmedchemlett.5b00489

Cited by 15 publications

(19 citation statements)

References 37 publications

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“…Oligodendrocyte precursor cells within demyelinated lesions of CXCR2 null mice proliferated earlier and more vigorously [34]. CXCR2 also represents a viable target for promoting remyelination following traumatic injury, dysmyelinating conditions, or infection [35–38].…”

Section: Discussionmentioning

confidence: 99%

Effect of CXCR2 Inhibition on Behavioral Outcomes and Pathology in Rat Model of Neuromyelitis Optica

Jones

Lévy

2018

Journal of Immunology Research

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Objective To reduce immune-mediated damage in a rat model of neuromyelitis optica (NMO) by blocking neutrophil migration using SCH527123, a drug that inhibits CXCR2. Background Neuromyelitis optica is a relapsing autoimmune disease that preferentially targets the optic nerves and spinal cord leading to blindness and paralysis. Part of the immunopathogenesis of this disease is thought to involve neutrophils, which are present within NMO lesions. We tested the effect of blocking neutrophil migration in an NMO rat model. Methods The Lewis rat model of NMO uses a myelin-reactive experimental autoimmune encephalomyelitis (EAE) background with passive transfer of pooled human antibody from patients with aquaporin-4 (AQP4) seropositive NMO at onset of EAE symptoms. We treated rats early in the course of EAE with CXCR2 inhibitor and assessed the extent of neutrophil infiltration into the spinal cord and the extent of AQP4 depletion. Results CXCR2 inhibitor decreased neutrophil migration into the spinal cord of AQP4 IgG-treated EAE rats. However, there was no difference in the acute behavioral signs of EAE or the extent and distribution of AQP4 lesions. This suggests that neutrophils are not centrally involved in the immunopathogenesis of the Lewis rat NMO disease model. Conclusions CXCR2 inhibitor blocks neutrophil migration into the spinal cord during EAE but does not significantly reduce inflammation or AQP4 lesions in the Lewis rat model of NMO.

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Section: Discussionmentioning

confidence: 99%

Effect of CXCR2 Inhibition on Behavioral Outcomes and Pathology in Rat Model of Neuromyelitis Optica

Jones

Lévy

2018

Journal of Immunology Research

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“…2-Azaspiro[3.3]heptanes used as piperidine isosteres are less common, and only limited examples have been reported. Of note, we observed the C -linked CXCR2 antagonist 27b (Figure ), reported to be about 2-fold more potent than 27a , but crucially for the project had 25-fold less brain penetration . While the authors invoked potential transporter effects, we would also hypothesize that the increased basicity of the spiro-analogue might have played an important role.…”

mentioning

confidence: 81%

“…Of note, we observed the C-linked CXCR2 antagonist 27b (Figure 7), reported to be about 2-fold more potent than 27a, but crucially for the project had 25-fold less brain penetration. 24 While the authors invoked potential transporter effects, we would also hypothesize that the increased basicity of the spiro-analogue might have played an important role. The topical TACE inhibitor 28b also provides an interesting example where the motif occupies a slightly different place in the molecule.…”

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confidence: 99%

Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a logD Lowering Twist

Degorce

Bodnarchuk

Scott

2019

ACS Med. Chem. Lett.

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We have conducted an analysis of azaspiro [3.3]heptanes used as replacements for morpholines, piperidines, and piperazines in a medicinal chemistry context. In most cases, introducing a spirocyclic center lowered the measured logD 7.4 of the corresponding molecules by as much as −1.0 relative to the more usual heterocycle. This may seem counterintuitive, as the net change in the molecule is the addition of a single carbon atom, but it may be rationalized in terms of increased basicity. An exception to this was found with N-linked 2-azaspiro[3.3]heptane, where logD 7.4 increased by as much as +0.5, consistent with the addition of carbon. During our investigation, we also concluded that azaspiro[3.3]heptanes are most likely not suitable bioisosteres for morpholines, piperidines, and piperazines, when not used as terminal groups, due to significant changes in their geometry.

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“…CXCR2, expressed in neutrophils and oligodendrocyte progenitor cells, is reported to promote demyelination leading to multiple sclerosis. Inhibition of CXCR2 by a CNS penetrating antagonist or conditional knockout of Cxcr2 improves remyelination in a mouse model 122 , 194 , 195 . Cxcr2 -/- mice were resistant to cuprizone-induced demylination as compared to Cxcr2 +/+ mice 120 .…”

Section: The Cxcl8-cxcr1/2 Axis In Inflammatory Diseasesmentioning

confidence: 99%

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

Ha¹,

Debnath²,

Neamati³

2017

Theranostics

555

464

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The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.

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Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders

Cited by 15 publications

References 37 publications

Effect of CXCR2 Inhibition on Behavioral Outcomes and Pathology in Rat Model of Neuromyelitis Optica

Effect of CXCR2 Inhibition on Behavioral Outcomes and Pathology in Rat Model of Neuromyelitis Optica

Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a logD Lowering Twist

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

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