Following a ligand-based drug design approach, a potent mixed formyl peptide receptor 1 (FPR1) and formyl peptide receptor-like 1 (FPRL1) agonist (14a) and a potent and specific FPRL1 agonist (14x) were identified. These compounds belong to a large series of pyridazin-3(2H)-one derivatives substituted with a methyl group at position 6 and a methoxy benzyl at position 4. At position 2, an acetamide side chain is essential for activity. Likewise, the presence of lipophilic and/or electronegative substituents in the position para to the aryl group at the end of the chain plays a critical role for activity. Affinity forFPR1 receptors was evaluated by measuring intracellular calcium flux in HL-60 cells transfected with FPR1, FPRL1, and FPRL2. Agonists were able to activate intracellular calcium mobilization and chemotaxis in human neutrophils. Themost potent chemotactic agent (EC50 =0.6 μM) was the mixed FPR/FPRL1 agonist 14h.

6-Methyl-2,4-disubstituted pyridazin-3(2H)-ones: a novel class of small-molecule agonists for formyl peptide receptors / A. CILIBRIZZI; M.T.QUINN; L.N. KIRPOTINA; I.A.SCHEPETKIN; J.HOLDERNESS; R.D.YE; M.J. RABIET; C.BIANCALANI; N. CESARI; A. GRAZIANO; C.VERGELLI; S.PIERETTI; V.DAL PIAZ; M.P.GIOVANNONI.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - ELETTRONICO. - 52:(2009), pp. 5044-5057.

6-Methyl-2,4-disubstituted pyridazin-3(2H)-ones: a novel class of small-molecule agonists for formyl peptide receptors.

VERGELLI, CLAUDIA;DAL PIAZ, VITTORIO;GIOVANNONI, MARIA PAOLA
2009

Abstract

Following a ligand-based drug design approach, a potent mixed formyl peptide receptor 1 (FPR1) and formyl peptide receptor-like 1 (FPRL1) agonist (14a) and a potent and specific FPRL1 agonist (14x) were identified. These compounds belong to a large series of pyridazin-3(2H)-one derivatives substituted with a methyl group at position 6 and a methoxy benzyl at position 4. At position 2, an acetamide side chain is essential for activity. Likewise, the presence of lipophilic and/or electronegative substituents in the position para to the aryl group at the end of the chain plays a critical role for activity. Affinity forFPR1 receptors was evaluated by measuring intracellular calcium flux in HL-60 cells transfected with FPR1, FPRL1, and FPRL2. Agonists were able to activate intracellular calcium mobilization and chemotaxis in human neutrophils. Themost potent chemotactic agent (EC50 =0.6 μM) was the mixed FPR/FPRL1 agonist 14h.
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A. CILIBRIZZI; M.T.QUINN; L.N. KIRPOTINA; I.A.SCHEPETKIN; J.HOLDERNESS; R.D.YE; M.J. RABIET; C.BIANCALANI; N. CESARI; A. GRAZIANO; C.VERGELLI; S.PIERETTI; V.DAL PIAZ; M.P.GIOVANNONI.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/372796
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