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

Abstract

Formyl peptide receptors (FPRs) are G-protein-coupled receptors that play an important role in the regulation of inflammatory process and cellular dysfunction. In humans, three different isoforms are expressed (FPR1, FPR2 and FPR3). FPR2 appears to be directly involved in the resolution of inflammation (ROI), an active process carried out by specific pro-resolving mediators that modulate specific receptors. Previously, we identified 2-arylacetamido pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of mixed-agonists for the three isoforms. Here, we report a new series of 2-arylacetamido pyridazinones substituted at position 5 and their development as FPR agonists. We also synthesized a new series of 2-oxothiazolones bearing a 4-bromophenylacetamido fragment, which was fundamental for activity in the pyridazinone series. The compounds of most interest were 4a, a potent, mixed FPR agonist recognized by all three isotypes (FPR1 EC50 = 19 nM, FPR2 EC50 = 43 nM, FPR3 EC50 = 40 nM), and 4b, which had potent activity and a preference for FPR2 (EC50 = 13 nM). These novel 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

“…In order to evaluate potential differences in interaction with FPRs of highly active pyridazinones EC10 (Vergelli et al., 2016 ) and EC3 (Vergelli et al., 2017 ) and pyridinone 2a (Crocetti et al., 2020 ) on the one hand, and moderately active or inactive newly synthesized compounds containing the pyrazole or pyrazolone scaffolds on the other hand, we evaluated docking of EC3 , EC10 , 2a , 4e , 7a , 10 , and 15 into the FPR1 and FPR2 binding sites. The FPR1 and FPR2 geometries reported by Zhuang et al., 2020 were used as sources of the receptor structures for docking.…”

“…In particular, EC3 (Vergelli et al., 2017 ) has H‐bond interactions via the oxygen of the 3‐methoxyphenyl group and the acetamido carbonyl oxygen with Gln258 and Arg205, respectively. The NH of the same acetamido chain interacts with Asp106, Figure 8 panel a.…”

“…They are small molecules with different scaffolds, all displaying a common N‐(4‐bromophenyl) acetamide fragment. The most potent compounds, with EC 50 values in nanomolar or submicromolar range, are the pyridazin‐3(2H)‐one derivatives EC10 (Vergelli et al., 2016 ), EC3 (Vergelli et al., 2017 ), and the pyridinone 2a (Crocetti et al., 2020 ; Figure 2 ). These three compounds were also evaluated in vivo in a rat model of rheumatoid arthritis and were found to exhibit anti‐inflammatory activity (Crocetti et al., 2020 ).…”

Peptide Mimetics: Fast‐Forward Look

“…For example, synthetic FPR antagonists were shown to reduce ischemia/ reperfusion injury in mouse stroke model [Smith et al, 2005]. Recently, several phenylacetamidosubstituted heterocycles were described as potent FPR agonists [Vergelli et al, 2017].…”

Developing selective FPR2 agonists can be a potential approach to treat moderate to severe asthma

“…An increasing number of both peptide and non-peptide FPR1/2 dual agonists are being reported in the literature with demonstrated anti-inflammatory and immunological properties (Kao et al, 2014; Boulay et al, 1990, Bürli et al, 2006; Vacchelli et al, 2020; Qin et al, 2017; Cattaneo et al, 2019; Cilibrizzi et al, 2013; Cilibrizzi et al, 2009; Cilibrizzi et al, 2012; Crocetti et al, 2013; Giovannoni et al, 2013; Vergelli et al, 2016; Vergelli et al, 2017; Migeotte et al, 2006; Odobasic et al, 2018), none of them however have reached clinics so far. We, therefore, first conducted a careful literature analysis to understand the biology of FPR family members and if there are any functional differences between them, followed by in-house efforts to identify molecules with a desirable biological profile.…”