Pyridinone Derivatives as Interesting Formyl Peptide Receptor (FPR) Agonists for the Treatment of Rheumatoid Arthritis.

Letizia Crocetti,Lorenzo Di Cesare Mannelli,Carla Ghelardini,Maria Paola Giovannoni,Liliya N Kirpotina,Igor A Schepetkin,Claudia Vergelli,Andrei I Khlebnikov,Gabriella Guerrini,Mark T Quinn,Elena Lucarini

doi:10.3390/molecules26216583

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the research has been directed in recent years towards new possible targets. Among these targets, N-formyl peptide receptors (FPRs) are of particular interest. Recently, the mixed FPR1/FPR2 agonist Cpd43, the FPR2 agonist AT-01-KG, and the pyridine derivative AMC3 have been shown to be effective in RA animal models. As an extension of this research, we report here a new series of pyridinone derivatives containing the (substituted)phenyl acetamide chain, which was found to be essential for activity, but with different substitutions at position 5 of the scaffold. The biological results were also supported by molecular modeling studies and additional pharmacological tests on AMC3 have been performed in a rat model of RA, by repeating the treatments of the animals with 10 mg/kg/day of compound by 1 week.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by autoantibody production, joint inflammation, synovial hyperplasia, cartilage damage, and bone destruction, as well as cardiovascular, hematological, and pulmonary complications [1]
The insertion of alkyl esters, the maintenance of the methoxyphenyl group variously spaced from the pyridinone scaffold with ester or carbonyl groups, as well as the presence of a hydroxy carbonyl group all resulted in retention of FPR1/FPR2 mixed agonist activity (Table 1)
We report new pyridinone derivatives as analogues of the potent formyl peptide receptors (FPRs) agonists AMC3 and AMC4, previously described by us

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by autoantibody production, joint inflammation, synovial hyperplasia, cartilage damage, and bone destruction, as well as cardiovascular, hematological, and pulmonary complications [1]. The powerful and selective biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) have been added to the pharmaceutical armamentarium, but these drugs have serious side effects and are very expensive [3]. These therapeutic approaches fail in a substantial number of patients; there is significant interest in alternative targets for RA treatment [4].

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