Synthesis and Pharmacological Evaluation of New Pyridazin‐Based Thioderivatives as Formyl Peptide Receptor (<scp>FPR</scp>) Agonists

Crocetti, Letizia; Vergelli, Claudia; Cilibrizzi, Agostino; Graziano, Alessia; Khlebnikov, Аndrei I.; Kirpotina, Liliya N.; Schepetkin, Igor A.; Quinn, Mark T.; Giovannoni, Maria Paola

doi:10.1002/ddr.21076

Cited by 22 publications

(32 citation statements)

References 45 publications

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“…The homology model derived from the rhodopsin template shows that the FPR1 ligand binding site comprises two channels, two cavities, and the bottom [ 145 ]. Several amino acids are found to be involved in the interaction of FPR1 with agonists, including Asn 192 , Thr 199 , Arg 205 , Tyr 257 , and Thr 265 [ 80 , 145 , 146 , 212 ]. Docking studies with FPR1 non-peptide antagonists (including the bile acids DCA and CDCA) suggested that Thr 177 , Tyr 257 , and Thr 265 are involved in the formation of three stable H-bond interactions with DCA and CDCA in the docked pose [ 224 , 225 ].…”

Section: Structural Basis For Ligand Detectionmentioning

confidence: 99%

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Ye²

2017

Molecules

219

216

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The formyl peptide receptors (FPRs) are G protein-coupled receptors that transduce chemotactic signals in phagocytes and mediate host-defense as well as inflammatory responses including cell adhesion, directed migration, granule release and superoxide production. In recent years, the cellular distribution and biological functions of FPRs have expanded to include additional roles in homeostasis of organ functions and modulation of inflammation. In a prototype, FPRs recognize peptides containing N-formylated methionine such as those produced in bacteria and mitochondria, thereby serving as pattern recognition receptors. The repertoire of FPR ligands, however, has expanded rapidly to include not only N-formyl peptides from microbes but also non-formyl peptides of microbial and host origins, synthetic small molecules and an eicosanoid. How these chemically diverse ligands are recognized by the three human FPRs (FPR1, FPR2 and FPR3) and their murine equivalents is largely unclear. In the absence of crystal structures for the FPRs, site-directed mutagenesis, computer-aided ligand docking and structural simulation have led to the identification of amino acids within FPR1 and FPR2 that interact with several formyl peptides. This review article summarizes the progress made in the understanding of FPR ligand diversity as well as ligand recognition mechanisms used by these receptors.

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Section: Structural Basis For Ligand Detectionmentioning

confidence: 99%

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Ye²

2017

Molecules

219

216

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“…Additionally, they have R substitutions of SCH3 and OCH3, as well as R1 substitutions of I and SCH3, respectively. Both R and R1 substitutions are on substituted benzene rings [117]. (See Table 6 for the list of synthetic/small molecule non-peptide agonists).…”

Section: Synthetic Peptides and Non-peptide Small Moleculesmentioning

confidence: 99%

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

Krepel

Wang

2019

IJMS

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Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention.

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“…In previous studies, we identified several pyridazin-3( 2H )-one-based derivatives that showed an interesting profile as FPR agonists, combining an appreciable potency and differential selectivity toward the three human FPR isoforms [17–21]. Key requirements for agonist activity of this class of compounds were the presence of a 4-bromophenylacetamide side chain at the N-2 position of the scaffold [17, 19] and the presence of a methyl group at C-6 [20].…”

Section: Introductionmentioning

confidence: 99%

2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists

Vergelli

Schepetkin

Ciciani

et al. 2016

Bioorganic & Medicinal Chemistry

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N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.

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Synthesis and Pharmacological Evaluation of New Pyridazin‐Based Thioderivatives as Formyl Peptide Receptor (FPR) Agonists

Cited by 22 publications

References 45 publications

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists

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