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. Several 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.

Keywords: Ca(2+) mobilization; Chiral agonist; Formyl peptide receptor; Metabolic stability; Neutrophil; Ureidopropanamide.

Figure 1

Structural Formulas of Non-Peptidic FPR1/FPR2 Agonists

Figure 2

Structural Formulas of the Bombesin-Related Receptor BB1 and BB2 antagonists PD-176252 (7) and PD-168368 (8)

Figure 3

Overlay of molecular conformations of enantiomer pair (R)-9c/(S)-9c with the best fit to the geometry of the FPR2 template. Superimpositions of the conformations to the template were refined by the simplex optimization algorithm incorporated in FieldAlign. Field points are colored as follows: blue, electron-rich (negative); red, electron-deficient (positive); yellow, van der Waals attractive (steric). All field points belonging to FPR templates are icosaedre shaped, and field points, belonging to (R)-9c/(S)-9c are spherical. The hydrophobic field surface is colored in orange. The three hydrophobic surfaces are marked as H1, H₂, and H₃ in accordance with our previously reported FPR2 pharmacophore model.

Scheme 1

Synthesis of Derivative 15aa ^aReagents: (A) NaH (60% oil dispersion), methyl iodide; (B) 3-chloroperbenzoic acid, Na₂SO₄; (C) acetic anhydride; (D) KOH, MeOH; (E) SOCl₂; (F) KCN.

Scheme 2

Synthesis of the Target Compoundsa ^aReagents: (A) NaH (60% oil dispersion), 1,5-dibromopentane; (B) Raney-nickel, H₂ (5 atm), 2M ethanolic NH₃; (C) (R)- or (S)-Boc-tryptophan activated with N, N’-carbonyldiimidazole; (D) trifluoroacetic acid; (E) 4-methoxyphenylisocyanate.