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

Enza Lacivita, Igor A. Schepetkin, Madia L. Stama, Liliya N. Kirpotina, Nicola A. Colabufo, Roberto Perrone, Andrey Ivanovich Khlebnikov, Mark T. Quinn, Marcello Leopoldo

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3913-3924
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number14
DOIs
Publication statusPublished - 11 Sep 2014

Fingerprint

Formyl Peptide Receptor
Molecular modeling
G-Protein-Coupled Receptors
Derivatives
human FPR2 protein
Pharmaceutical Preparations

Keywords

  • Ca<sup>2+</sup> mobilization
  • Chiral agonist
  • Formyl peptide receptor
  • Metabolic stability
  • Neutrophil
  • Ureidopropanamide

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2. / Lacivita, Enza; Schepetkin, Igor A.; Stama, Madia L.; Kirpotina, Liliya N.; Colabufo, Nicola A.; Perrone, Roberto; Khlebnikov, Andrey Ivanovich; Quinn, Mark T.; Leopoldo, Marcello.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 14, 11.09.2014, p. 3913-3924.

Research output: Contribution to journalArticle

Lacivita, Enza ; Schepetkin, Igor A. ; Stama, Madia L. ; Kirpotina, Liliya N. ; Colabufo, Nicola A. ; Perrone, Roberto ; Khlebnikov, Andrey Ivanovich ; Quinn, Mark T. ; Leopoldo, Marcello. / Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 23, No. 14. pp. 3913-3924.
@article{23424fe57c404f23a67bce0f387da785,
title = "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<sup>2+</sup> mobilization, Chiral agonist, Formyl peptide receptor, Metabolic stability, Neutrophil, Ureidopropanamide",
author = "Enza Lacivita and Schepetkin, {Igor A.} and Stama, {Madia L.} and Kirpotina, {Liliya N.} and Colabufo, {Nicola A.} and Roberto Perrone and Khlebnikov, {Andrey Ivanovich} and Quinn, {Mark T.} and Marcello Leopoldo",
year = "2014",
month = "9",
day = "11",
doi = "10.1016/j.bmc.2014.12.007",
language = "English",
volume = "23",
pages = "3913--3924",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "14",

}

TY - JOUR

T1 - Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2

AU - Lacivita, Enza

AU - Schepetkin, Igor A.

AU - Stama, Madia L.

AU - Kirpotina, Liliya N.

AU - Colabufo, Nicola A.

AU - Perrone, Roberto

AU - Khlebnikov, Andrey Ivanovich

AU - Quinn, Mark T.

AU - Leopoldo, Marcello

PY - 2014/9/11

Y1 - 2014/9/11

N2 - 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.

AB - 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.

KW - Ca<sup>2+</sup> mobilization

KW - Chiral agonist

KW - Formyl peptide receptor

KW - Metabolic stability

KW - Neutrophil

KW - Ureidopropanamide

UR - http://www.scopus.com/inward/record.url?scp=84930870655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930870655&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2014.12.007

DO - 10.1016/j.bmc.2014.12.007

M3 - Article

AN - SCOPUS:84930870655

VL - 23

SP - 3913

EP - 3924

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 14

ER -