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

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(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.

Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N‐formyl peptide receptors agonists

“…All new compounds were evaluated for their ability to induce intracellular Ca 2+ flux in human neutrophils (hPMN) and in human HL-60 cells transfected with FPR1 and FPR2, and the results are reported as EC 50 values in Tables 2 and 3 using as reference compounds fMLF (FPR1 agonist), WKYMVm (FPR2 agonist), and the previously described agonists EC3 and EC10 (Vergelli et al, 2016(Vergelli et al, , 2017. All compounds were also evaluated in wildtype non-transfected HL-60 cells and were found to be inactive.…”

Synthesis of Five‐ and Six‐Membered N‐Phenylacetamido Substituted Heterocycles as Formyl Peptide Receptor Agonists

“…Key requirements for activity were the presence of a methyl group at position 6 of the pyridazinone ring, a 4‐bromophenylacetamide moiety at N ‐2, and a benzyl/aniline group at position 4 of the scaffold. In the series of 4‐anilino derivatives, we identified some compounds with good potency and with a moderate preference for FPR2 subtype [Vergelli et al, ]. In the present article, we further investigated 4‐benzylpyridazinones derivatives as isosteres of the 4‐anilino derivatives and examine their structure‐activity relationships [Vergelli et al, ], as well as several derivatives lacking a benzyl fragment at position 4.…”

“…In the series of 4‐anilino derivatives, we identified some compounds with good potency and with a moderate preference for FPR2 subtype [Vergelli et al, ]. In the present article, we further investigated 4‐benzylpyridazinones derivatives as isosteres of the 4‐anilino derivatives and examine their structure‐activity relationships [Vergelli et al, ], as well as several derivatives lacking a benzyl fragment at position 4. We also synthesized and evaluated a series of 2‐oxothiazolones by maintaining the 4‐bromophenylacetamide side fragment.…”

“…Our research in the field of FPR ligands led to the identification of a large number of pyridazin-3(2H)-one derivatives that were mixed FPR1/FPR2 agonists (Fig. 1, general structure A) [Cilibrizzi et al, 2009[Cilibrizzi et al, , 2012Cilibrizzi et al, 2013;Crocetti et al, 2013;Giovannoni et al, 2013, Vergelli et al, 2016. Key requirements for activity were the presence of a methyl group at position 6 of the pyridazinone ring, a 4-bromophenylacetamide moiety at N-2, and a benzyl/ aniline group at position 4 of the scaffold.…”

Correspondence: Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury

“…Moreover, a high variability of ligand activity data has been also reported for FPRs when comparing species (e.g. human FPRs vs murine Fprs, expressed in different cell lines) 16 . With regard to the reported biased effects of racemate 17b, the experimental evidence provided in ref.…”