Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2

Abstract

N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists, that were designed starting from our lead agonist (S )-3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N -[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Various of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds.

Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation

“…Among the screened compounds, the enantiomeric pair ( R )- and ( S )- 6 , in which the cyclohexane ring was replaced with the cyclopropane ring, had a percentage of recovery (15% and 11%, respectively) higher than that of 5 (4%) (Table 1). In addition, the phenylcyclopropylmethyl moiety is more synthetically accessible as compared to the (5-methoxypyridin-2-yl)cyclohexylmethyl moiety of compound 5 [34]. Regarding interaction with FPR2, ( R )- 6 was previously characterized as a weak FPR2 antagonist, whereas ( S )- 6 was able to induce Ca 2+ mobilization, albeit with low potency (EC 50 = 7.6 μM) [33].…”

“…Recently, we reported the identification of a group of 3-(1 H -indol-3-yl)-2-[3-(4-substituted-phenyl)ureido]propanamide derivatives as agonists of human FPR2, exemplified by compound 5 (Table 1, Chart 1) [33,34]. The above agonists were characterized for their ability to induce intracellular Ca 2+ release.…”

“…Toward this aim, we have modified the structural framework of 5 taking into account that this agonist showed very low stability toward oxidative metabolism and was rapidly degraded after incubation with rat liver microsomes, thus implying that 5 has a pharmacokinetic profile not compatible with in vivo studies [34]. …”

Radiosynthesis and in vivo Evaluation of Carbon‐11 (2S)‐3‐(1H‐Indol‐3‐yl)‐2‐{[(4‐methoxyphenyl)carbamoyl]amino}‐N‐{[1‐(5‐methoxypyridin‐2‐yl)cyclohexyl]methyl}propanamide: An Attempt to Visualize Brain Formyl Peptide Receptors in Mouse Models of Neuroinflammation

“…In this regard, in parallel with the in vivo evaluation of ( S )‐[ 11 C]‐ 1 , we evaluated rat liver microsomal stability of a small set of ureidopropanamides, including ( S )‐ 1 and PD‐176252. All the studied compounds were rapidly metabolized by rat liver microsomes showing very short half‐lives . These findings could explain the high radioactivity levels observed in the liver.…”

“…The desmethyl precursor for 11 C‐radiolabeling ( S )‐ 5 was easily prepared as shown in Scheme . ( S )‐Boc‐tryptophan was activated with N , N ′‐carbonyldiimidazole and condensed with the amine 2 , prepared as previously reported , to give the Boc‐protected derivative ( S )‐ 3 . Subsequently, the latter compound was deprotected with trifluoroacetic acid to give the amine ( S )‐ 4 , which was condensed with 4‐aminophenol in the presence of N , N ′‐carbonyldiimidazole to give the ureido derivative ( S )‐ 5 in good yield.…”