Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents

Bürli, Roland W.; Xu, Han; Zou, Xiaoming; Muller, Kristine; Golden, Jennifer E.; Frohn, Mike; Adlam, Matthew; Plant, Matthew; Wong, Min‐Liang; McElvain, Michele; Regal, Kelly; Viswanadhan, Vellarkad N.; Tagari, Philip; Hungate, Randall W.

doi:10.1016/j.bmcl.2006.04.068

Cited by 110 publications

(106 citation statements)

References 24 publications

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“…It might well be that ligands may behave differently in functional assays because of their intrinsic ability to induce different receptor conformational changes, but we have not looked into this issue since compound 3 was not among the most potent neutrophil activators and thus not further investigated. Compound 4 is a pyrazolone originally described as an FPR2 agonist that dose 19 dependently inhibit chemotaxis of human neutrophils in response to fMLF and IL8 [19]. This is in accordance with earlier studies suggesting that FPR2 is a down-regulating receptor when interacting with the lipoxygenase-derived eicosanoid lipoxin A 4 or peptides derived from the N-terminus of the calcium regulated protein annexin I [11,43].…”

Section: Discussionsupporting

confidence: 85%

“…The other part (an additional 10 000 compounds) was based on reference compounds collected from the literature ( [19], http://www.wipo.int/pctdb/en/wo.jsp?wo=2005047899), and used as input to computational techniques allowing us to detect compounds with similar properties. In order to do this a pharmacophore was built in Phase [20] and it consisted of a central acceptor/donor pair flanked on one side of an acceptor and a hydrophobic group and on the other side by one aromatic group and one hydrophobic group (see supplementary Fig 1).…”

Section: Methodsmentioning

confidence: 99%

“…All the agonists were found to activate the neutrophils to produce superoxide. The three most potent agonists, one earlier described pyrazolone compound [19] and two new compound, were further characterized and found to be insensitive to inactivation by oxidants and possess all the functional characteristics of earlier described pro-inflammatory peptide agonists. Upon binding to human neutrophils, they induce granule mobilization, directional cellular migration and production of superoxide anion.…”

Section: Introductionmentioning

confidence: 90%

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Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

Forsman

Kalderén

Nordin

et al. 2011

Biochemical Pharmacology

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The neutrophil formyl peptide receptors (FPR1 and FPR2) are G-protein coupled receptors that can induce pro-inflammatory as well as anti-inflammatory activities when activated. Accordingly, these receptors may become therapeutic targets for the development of novel drugs to be used for reducing the inflammation induced injuries in asthma, rheumatoid arthritis, Alzheimer's disease, cardiovascular diseases and traumatic shock. We screened a library of more then 50 K small compounds for an ability of the compounds to induce a transient rise in intracellular Ca 2+ in cells transfected to express FPR2 (earlier called FPRL1 or the lipoxin A 4 receptor). Ten agonists hits were selected for further analysis representing different chemical series and five new together with five earlier described molecules were further profiled.. Compounds 1 -10 gave rise to a calcium response in the FPR2 transfectants with EC 50 values ranging from 4 x 10 -9 M to 2 x 10 -7 M. All 10 compounds activated human neutrophils to release superoxide , and based on the potency of their activity, the three most potent activators of the neutrophil NADPH-oxidase were further characterized. These three agonists were largely resistant to inactivation by neutrophil produced reactive oxygen species and shown to trigger the same functional repertoire in neutrophils as earlier described peptide agonists. Accordingly they induced chemotaxis, granule mobilization and secretion of superoxide. Interestingly, the oxidase activity was largely inhibited by cyclosporine H, an FPR1 selective antagonist, but not by PBP10, an FPR2 selective inhibitor, suggesting that FPR1 is the preferred receptor in neutrophils for all three agonists.

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Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

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Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

Forsman

Kalderén

Nordin

et al. 2011

Biochemical Pharmacology

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“…Compound 43 (Cpd43) is a low MW compound synthesized as an agonist for FPR2 (Burli et al, 2006) and has been shown to have this function in human leukocytes (Sogawa et al, 2009;. In vivo, Cpd43 exerts anti-inflammatory effects in murine ear inflammation and air-pouch models, which require FPR2 (Burli et al, 2006;Dufton et al, 2010;Sogawa et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In vivo, Cpd43 exerts anti-inflammatory effects in murine ear inflammation and air-pouch models, which require FPR2 (Burli et al, 2006;Dufton et al, 2010;Sogawa et al, 2011). Mutation studies have identified specific domains in FPR2, which are required for the action of Cpd43 (Bena et al, 2012), but in human neutrophils, Cpd43 has also been reported to interact with FPR1 (Forsman et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Kao

Jia

et al. 2014

British J Pharmacology

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Background and PurposeAnnexin A1 (AnxA1) is an endogenous anti‐inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune‐mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast‐like synoviocytes (FLS).Experimental ApproachArthritis was induced by injection of K/BxN serum at day 0 and 2 in wild‐type (WT) or AnxA1−/− mice and clinical and histopathological manifestations measured 8–11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg−1 i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL‐induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages.Key ResultsTreatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF‐α and osteoclast‐associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL‐6 secretion by mouse macrophages. In human RA joint‐derived FLS and monocyte‐derived macrophages, Cpd43 treatment inhibited IL‐6 release, while blocking FPR2 or silencing AnxA1 increased this release.Conclusions and ImplicationsThe FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti‐inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA.

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Asymmetric Addition and Cycloaddition Reactions with Ylidene‐Five‐Membered Heterocycles

et al. 2021

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Five‐membered heterocycles bearing an exocyclic double bond have been successfully used as substrates in asymmetric addition and cycloaddition reactions. Ylidene‐heterocycles are attractive substrates due to their high functionalization and the presence of an electrophilic conjugated exocyclic double bound that can participate in nucleophilic addition reactions as well as cycloaddition reactions, which may be triggered by the formation of aromatic intermediates or products in many cases. During the last decades, catalytic methodologies have been developed using ylidene‐heterocycles as substrates in order to synthesize useful optically active heterocyclic derivatives. 4‐Ylidene‐pyrazol‐5‐ones, isoxazolin‐5‐ones, 2,3‐dioxopyrrolidines, rhodanines, oxazolidindiones, Erlenmeyer‐Ploch azlactones and 5‐ylidene‐thiazolones have been successfully used as substrates in asymmetric reactions. This review collects the powerful research in asymmetric addition and cycloaddition reactions where ylidene‐five‐membered heterocycles have been used.

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Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents

Cited by 110 publications

References 24 publications

Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Asymmetric Addition and Cycloaddition Reactions with Ylidene‐Five‐Membered Heterocycles

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