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Andrei I Khlebnikov - One of the best experts on this subject based on the ideXlab platform.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
Claudia Vergelli - One of the best experts on this subject based on the ideXlab platform.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
David Selwood - One of the best experts on this subject based on the ideXlab platform.
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Biophysical screening methods for extracellular domain Peptide Receptors, application to natriuretic Peptide receptor C ligands
Chemical Biology & Drug Design, 2018Co-Authors: Daniel Conole, Samuel H. Myers, Filipa Mota, Adrian J. Hobbs, David SelwoodAbstract:Endothelium-derived C-type natriuretic Peptide possesses cytoprotective and anti-atherogenic functions that regulate vascular homeostasis. The vasoprotective effects of C-type natriuretic Peptide are somewhat mediated by the natriuretic Peptide receptor C, suggesting that this receptor represents a novel therapeutic target for the treatment of cardiovascular diseases. In order to facilitate our drug discovery efforts, we have optimized an array of biophysical methods including surface plasmon resonance, fluorescence polarization and thermal shift assays to aid in the design, assessment and characterization of small molecule agonist interactions with natriuretic Peptide Receptors. Assay conditions are investigated to explore the feasibility and dynamic range of each method, and Peptide-based agonists and antagonists are used as controls to validate these conditions. Once established, each technique was compared and contrasted with respect to their drug discovery utility. We foresee that such techniques will facilitate the discovery and development of potential therapeutic agents for NPR-C and other large extracellular domain membrane Receptors.
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Biophysical screening methods for extracellular domain Peptide Receptors, application to natriuretic Peptide receptor C ligands.
'Wiley', 2018Co-Authors: Conole D, Sh Myers, Mota F, Aj Hobbs, David SelwoodAbstract:This is the peer reviewed version of the following article:Conole, D., et al. "Biophysical screening methods for extracellular domain Peptide Receptors, application to natriuretic Peptide receptor C ligands." Chemical Biology and Drug Design 0(ja)., which has been published in final form at [https://doi.org/10.1111/cbdd.13395. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsEndothelium-derived C-type natriuretic Peptide possesses cytoprotective and anti-atherogenic functions that regulate vascular homeostasis. The vasoprotective effects of C-type natriuretic Peptide are somewhat mediated by the natriuretic Peptide receptor C, suggesting that this receptor represents a novel therapeutic target for the treatment of cardiovascular diseases. In order to facilitate our drug discovery efforts, we have optimized an array of biophysical methods including surface plasmon resonance, fluorescence polarization and thermal shift assays to aid in the design, assessment and characterization of small molecule agonist interactions with natriuretic Peptide Receptors. Assay conditions are investigated to explore the feasibility and dynamic range of each method, and Peptide-based agonists and antagonists are used as controls to validate these conditions. Once established, each technique was compared and contrasted with respect to their drug discovery utility. We foresee that such techniques will facilitate the discovery and development of potential therapeutic agents for NPR-C and other large extracellular domain membrane Receptors.This work was funded by a translational award from the British Heart Foundation(TG/15/3/31692), Wellcome Trust grants (084449/Z/07/Z and 078496/Z/05/Z), UCL Business PLC (PoC-12-007)and an Apollo Therapeutics one-off experiment fun
Liliya N Kirpotina - One of the best experts on this subject based on the ideXlab platform.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
Igor A Schepetkin - One of the best experts on this subject based on the ideXlab platform.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
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2 arylacetamido 4 phenylamino 5 substituted pyridazinones as formyl Peptide Receptors agonists
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Claudia Vergelli, G Ciciani, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Liliya N Kirpotina, Maria Paola Giovannoni, Agostino Cilibrizzi, Igor A Schepetkin, Andrei I KhlebnikovAbstract:Abstract 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(2 H )-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(2 H )-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 EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.