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

摘要

Abstract Formyl peptide receptor2 (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. Graphical abstract Display Omitted Highlights ? Novel FPR2 agonists were synthesized and in?vitro metabolic stability was evaluated. ? The most interesting compounds showed in?vitro neuroprotective properties. ? ( S )- 17 reduced IL-1β and TNFα levels in LPS-stimulated primary rat microglia cells. ? ( S )- 17 showed good permeation rate in an in?vitro model of blood brain barrier. ? FPR2 agonists have potential for resolving neuroinflammation in CNS disorders.