FPR2/ALXR Agonists and the Resolution of Inflammation

Corminboeuf, Olivier; Leroy, Xavier

doi:10.1021/jm501051x

Cited by 113 publications

(99 citation statements)

References 202 publications

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“…This structural modification was inspired by the observation that different aminoacid cores were well tolerated in other FPR2 agonists with ureidopropanamide structure [28]. For this purpose, we selected the commercially available 4-cyanophenylalanine and 3-pyridylalanine.…”

Section: Resultsmentioning

confidence: 99%

“…A wide range of chemically diverse non-peptidic FPR agonists have been identified so far [28], including benzimidazole derivatives exemplified by compound 1 [29], N -phenylurea derivatives (compound 2 ) [30], quinazolinones derivatives such as the highly specific non-peptide FPR2 agonist Quin-C1 ( 3 ) [31], and pyrazolone derivatives like the mixed FPR1/FPR2 agonist 4 (designated in most of publications as “Compound 43”) [32] (see Chart 1). Recently, we reported the identification of a group of 3-(1 H -indol-3-yl)-2-[3-(4-substituted-phenyl)ureido]propanamide derivatives as agonists of human FPR2, exemplified by compound 5 (Table 1, Chart 1) [33,34].…”

Section: Introductionmentioning

confidence: 99%

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Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation

Stama

Ślusarczyk

Lacivita

et al. 2017

European Journal of Medicinal Chemistry

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Formyl peptide receptor-2 (FPR2) is a G-protein coupled receptor that plays critical roles in inflammatory reactions. FPR2-specific interaction can be possibly used to facilitate the resolution of pathological inflammatory responses by enhancing endogenous anti-inflammation systems. Starting from our lead agonist 5, we designed new ureidopropanamides derivatives able to activate FPR2 in transfected cells and human neutrophils. The new FPR2 agonists showed good stability towards oxidative metabolism in vitro. Moreover, selected compounds showed anti-inflammatory properties in LPS-stimulated rat primary microglial cells. (S)-3-(4-Cyanophenyl)-N-[[1-(3-chloro-4-fluorophenyl)cyclopropyl]methyl]-2-[3-(4-fluorophenyl)ureido]propanamide ((S)-17) emerged as prospective pharmacological tool to study the effects of FPR2 activation in the central nervous system (CNS) being able to reduce IL-1β and TNF-α levels in LPS-stimulated microglial cells and showing good permeation rate in hCMEC/D3 cells, an in vitro model of blood brain barrier. These results are very promising and can open new therapeutic perspectives in the treatment of CNS disorders characterized by neuroinflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation

Stama

Ślusarczyk

Lacivita

et al. 2017

European Journal of Medicinal Chemistry

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“…LXA 4 attenuates neutrophil chemotaxis, respiratory burst, adhesion, and transendothelial migration, facilitates neutrophil apoptosis, stimulates macrophage clearance of apoptotic cells, suppresses IL-8 production, enhances airway epithelial tight junction formation, and augments repair of the bronchial epithelia. However, stable agonist analogs have been generated that mimic the effects of LXA 4 , making clinical evaluation a possibility (35,36). The half-life of LXA 4 is short, which makes it unusable as a therapeutic.…”

Section: Lipoxins and Resolvinsmentioning

confidence: 99%

Considerations for the Conduct of Clinical Trials with Antiinflammatory Agents in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

et al. 2015

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Inflammation leads to lung destruction and loss of pulmonary function in patients with cystic fibrosis (CF). Drugs that modulate the cystic fibrosis transmembrane conductance regulator (CFTR) have recently been approved. Although the impact of CFTR modulators on sweat chloride and lung function are exciting, they have not yet demonstrated an effect on inflammation. Therefore, CF antiinflammatory drug development must continue. Unfortunately, the lack of clarity with this process has left investigators and industry sponsors frustrated. The Cystic Fibrosis Foundation established a working group in early 2014 to address this issue. There are many inflammatory processes disrupted in CF, and, therefore, there are many potential targets amenable to antiinflammatory therapy. Regardless of a drug's specific mechanism of action, it must ultimately affect the neutrophil or its products to impact CF. The working group concluded that before bringing new antiinflammatory drugs to clinical trial, preclinical safety studies must be conducted in disease-relevant models to assuage safety concerns. Furthermore, although studies of antiinflammatory therapies must first establish safety in adults, subsequent studies must involve children, as they are most likely to reap the most benefit. The working group also recommended that pharmacokinetic-pharmacodynamic studies and early-phase safety studies be performed before proceeding to larger studies of longer duration. In addition, innovative study designs may improve the likelihood of adequately assessing treatment response and mitigating risk before conducting multiyear studies. Learning from past experiences and incorporating this knowledge into new drug development programs will be instrumental in bringing new antiinflammatory therapies to patients.

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“…The other group opposing these proinflammatory effects in synovial tissue is formed by anti-inflammatory mediators such as 15-LOX, formyl peptide receptor (FPR2), and IL-10 [6, 7]. Previous studies demonstrated that 15-LOX metabolites have potent anti-inflammatory actions on rheumatoid inflammation [8].…”

Section: Introductionmentioning

confidence: 99%

Comparative Expression Analyses of Pro- versus Anti-Inflammatory Mediators within Synovium of Patients with Joint Trauma, Osteoarthritis, and Rheumatoid Arthritis

Al-madol

Shaqura

John

et al. 2017

Mediators of Inflammation

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Synovial injury and healing are complex processes including catabolic effects by proinflammatory cytokines and anabolic processes by anti-inflammatory mediators. Here we examined the expression of pro- versus anti-inflammatory mediators in synovium of patients with diagnostic arthroscopy (control), joint trauma (JT), osteoarthritis (OA), and rheumatoid arthritis (RA). Synovial samples from these patients were subjected to RT-PCR and double immunofluorescence confocal microscopy of pro- and anti-inflammatory mediators as well as immune cell markers. Interestingly, pro- and anti-inflammatory mediators were expressed predominantly in granulocytes in patients with JT and in macrophages, lymphocytes, and plasma cells in patients with OA and RA. Interestingly, parallel to the severity of inflammation, proinflammatory mediators IL-1β, TNF-α, and 5-LOX specific mRNA as well as immunoreactive (IR) cells were significantly more abundant in patients with RA and JT than in those with OA. However, anti-inflammatory mediators 15-LOX, FPR2, and IL-10 specific mRNA as well as IR cells were significantly more abundant in patients with OA than in those with JT and RA. These findings show that upregulation of proinflammatory mediators contributes to the predominantly catabolic inflammatory process in JT and RA synovium, whereas upregulation of anabolic anti-inflammatory mediators counteracts inflammation resulting in the inferior inflammatory process in OA synovium.

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FPR2/ALXR Agonists and the Resolution of Inflammation

Cited by 113 publications

References 202 publications

Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation

Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation

Considerations for the Conduct of Clinical Trials with Antiinflammatory Agents in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

Comparative Expression Analyses of Pro- versus Anti-Inflammatory Mediators within Synovium of Patients with Joint Trauma, Osteoarthritis, and Rheumatoid Arthritis

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