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

Abstract

Formyl peptide receptor-2 (FPR2) is a G-protein coupled receptor that plays critical roles in inflammatory reactions. FPR2-specific interaction can be possibly used to facilitate the resolution of pathological inflammatory responses by enhancing endogenous anti-inflammation systems. Starting from our lead agonist 5, we designed new ureidopropanamides derivatives able to activate FPR2 in transfected cells and human neutrophils. The new FPR2 agonists showed good stability towards oxidative metabolism in vitro. Moreover, selected compounds showed anti-inflammatory properties in LPS-stimulated rat primary microglial cells. (S)-3-(4-Cyanophenyl)-N-[[1-(3-chloro-4-fluorophenyl)cyclopropyl]methyl]-2-[3-(4-fluorophenyl)ureido]propanamide ((S)-17) emerged as prospective pharmacological tool to study the effects of FPR2 activation in the central nervous system (CNS) being able to reduce IL-1β and TNF-α levels in LPS-stimulated microglial cells and showing good permeation rate in hCMEC/D3 cells, an in vitro model of blood brain barrier. These results are very promising and can open new therapeutic perspectives in the treatment of CNS disorders characterized by neuroinflammation.

Functional N‐Formyl Peptide Receptor 2 (FPR2) Antagonists Based on the Ureidopropanamide Scaffold Have Potential To Protect Against Inflammation‐Associated Oxidative Stress

“…In addition, when the hydroxyl group was introduced at the 3-position, the resulting compound (( S )- 26 ) had an EC 50 value comparable to that of compound ( S )- 4 , whereas the 4-substituted derivative (( S )- 27 ) had slightly lower agonist potency as compared to ( S )- 4 . This trend was in line with our previous finding suggesting that the size and position of the substituent in this part of the molecule influences the interaction with FPR2 [33]. Finally, the ( R )-enantiomers 26 and 27 were not able to activate FPR1, whereas the (S)-enantiomers had EC 50 values comparable to that of compound ( S )- 4 .…”

“…In fact, ( R )- and ( S )- 25 exhibited EC 50 values comparable to those of compound ( R )- and ( S )- 4 at both FPR2 and FPR1, confirming our previous findings that a polar group is well tolerated in that position [30, 33]. When the hydroxyl substituent was introduced on the phenyl ring of the “right hand” of the molecule, different effects were observed depending on the position and the chirality of the molecule.…”

“…This result was quite unexpected because a previous structure-activity study indicated that different substituents, including polar ones such as NO 2 or CN, were well tolerated in that position [33]. Thus, it is likely that the introduction of an H-bond donor substituent is not tolerated in this part of the molecule.…”

“…Recently, we developed ureidopropanamide derivatives as agonists of human FPR2, exemplified by compounds ( R )- and ( S )- 4 (Figure 1) [30–33]. Regarding FPR2 antagonists, several peptide [9] and peptidomimetic antagonists [34], exemplified by compound 5 , have been reported, whereas only a very limited number of small-molecule antagonists have been described so far (Figure 1).…”

“…We reasoned that insertion of the hydroxyl functionality in the ureidopropanamide scaffold could change the binding mode of the compounds and, therefore, could lead to the interconversion of their functional activity. To this end, we selected compounds ( R )- and ( S )- 4 (Table 1) and compound 2 (Table 2), which were previously characterized as FPR2 agonists in our laboratories, as starting points for the development of FPR2 antagonists with ureidopropanamide structures [28, 33]. …”