Further Studies on 2-arylacetamide Pyridazin-3(2H)-ones: Design, Synthesis and Evaluation of 4,6-disubstituted Analogs As Formyl Peptide Receptors (FPRs) Agonists

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2013 May 21

PMID 23685570

Citations 12

Authors

Maria Paola Giovannoni

Igor A Schepetkin

Agostino Cilibrizzi

Letizia Crocetti

Andrei I Khlebnikov

Claes Dahlgren

Alessia Graziano

Vittorio Dal Piaz

Liliya N Kirpotina

Serena Zerbinati

Claudia Vergelli

Mark T Quinn

Affiliations

Soon will be listed here.

Abstract

Formyl peptide receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca(2+) flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven formyl peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC50 values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca(2+) flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists.

Citing Articles

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References

Serhan C, Brain S, Buckley C, Gilroy D, Haslett C, ONeill L . Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007; 21(2):325-32. PMC: 3119634. DOI: 10.1096/fj.06-7227rev. View

Kelley L, Sternberg M . Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc. 2009; 4(3):363-71. DOI: 10.1038/nprot.2009.2. View

Khlebnikov A, Schepetkin I, Kirpotina L, Brive L, Dahlgren C, Jutila M . Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1. J Mol Model. 2011; 18(6):2831-43. PMC: 3314724. DOI: 10.1007/s00894-011-1307-x. View

OVEREND W, WIGGINS L . The conversion of sucrose into pyridazine derivatives; 3-sulphanilamido-6-methylpyridazine. J Chem Soc. 2010; :239-44. DOI: 10.1039/jr9470000239. View

Hu W, Ralay Ranaivo H, Roy S, Behanna H, Wing L, Munoz L . Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett. 2006; 17(2):414-8. PMC: 1868432. DOI: 10.1016/j.bmcl.2006.10.028. View

Miettinen H, MILLS J, Gripentrog J, Dratz E, Granger B, Jesaitis A . The ligand binding site of the formyl peptide receptor maps in the transmembrane region. J Immunol. 1997; 159(8):4045-54. View

Zhang L, Falla T . Host defense peptides for use as potential therapeutics. Curr Opin Investig Drugs. 2009; 10(2):164-71. View

Gavins F . Are formyl peptide receptors novel targets for therapeutic intervention in ischaemia-reperfusion injury?. Trends Pharmacol Sci. 2010; 31(6):266-76. PMC: 7112865. DOI: 10.1016/j.tips.2010.04.001. View

Baraldi P, Preti D, Aghazadeh Tabrizi M, Fruttarolo F, Saponaro G, Baraldi S . N(6)-[(hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5'-N-ethylcarboxamido-adenosines: the first example of adenosine-related structures with potent agonist activity at the human A(2B) adenosine receptor. Bioorg Med Chem. 2007; 15(7):2514-27. DOI: 10.1016/j.bmc.2007.01.055. View

10.

Costantino L, Rastelli G, Gamberini M, Giovannoni M, Dal Piaz V, Vianello P . Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors. J Med Chem. 1999; 42(11):1894-900. DOI: 10.1021/jm981107o. View

11.

Pieretti S, Di Giannuario A, De Felice M, Perretti M, Cirino G . Stimulus-dependent specificity for annexin 1 inhibition of the inflammatory nociceptive response: the involvement of the receptor for formylated peptides. Pain. 2004; 109(1-2):52-63. DOI: 10.1016/j.pain.2004.01.009. View

12.

Deflorian F, Jacobson K . Comparison of three GPCR structural templates for modeling of the P2Y12 nucleotide receptor. J Comput Aided Mol Des. 2011; 25(4):329-38. PMC: 3157290. DOI: 10.1007/s10822-011-9423-3. View

13.

Steiner G, Gries J, LENKE D . Synthesis and antihypertensive activity of new 6-heteroaryl-3-hydrazinopyridazine derivatives. J Med Chem. 1981; 24(1):59-63. DOI: 10.1021/jm00133a013. View

14.

Christophe T, Karlsson A, Boulay F, Dahlgren C . Phagocyte activation by Trp-Lys-Tyr-Met-Val-Met, acting through FPRL1/LXA4R, is not affected by lipoxin A4. Scand J Immunol. 2002; 56(5):470-6. DOI: 10.1046/j.1365-3083.2002.01149.x. View

15.

Forsman H, Kalderen C, Nordin A, Nordling E, Jensen A, Dahlgren C . Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library. Biochem Pharmacol. 2010; 81(3):402-11. DOI: 10.1016/j.bcp.2010.11.005. View

16.

Frohn M, Xu H, Zou X, Chang C, McElvaine M, Plant M . New 'chemical probes' to examine the role of the hFPRL1 (or ALXR) receptor in inflammation. Bioorg Med Chem Lett. 2007; 17(23):6633-7. DOI: 10.1016/j.bmcl.2007.09.043. View

17.

Dahlgren C, Christophe T, Boulay F, Madianos P, Rabiet M, Karlsson A . The synthetic chemoattractant Trp-Lys-Tyr-Met-Val-DMet activates neutrophils preferentially through the lipoxin A(4) receptor. Blood. 2000; 95(5):1810-8. View

18.

Ye R, Boulay F, Wang J, Dahlgren C, Gerard C, Parmentier M . International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev. 2009; 61(2):119-61. PMC: 2745437. DOI: 10.1124/pr.109.001578. View

19.

Cilibrizzi A, Quinn M, Kirpotina L, Schepetkin I, Holderness J, Ye R . 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones: a novel class of small-molecule agonists for formyl peptide receptors. J Med Chem. 2009; 52(16):5044-57. PMC: 2888720. DOI: 10.1021/jm900592h. View

20.

Kilby J, Hopkins S, Venetta T, DiMassimo B, Cloud G, Lee J . Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med. 1998; 4(11):1302-7. DOI: 10.1038/3293. View