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.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Madia L
authors.initials: ML
authors.lastname: Stama
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Department of Chemistry, Altai State Techical University, Barnaul, Russia; Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Khlebnikov
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004355:Drug Stability; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects; D018375:Neutrophil Activation / Q000187:drug effects; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000737:chemistry; D044067:Receptors, Lipoxin / Q000819:agonists* / Q000737:chemistry; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D000577:Amides; C105101:FPR2 protein, human; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D002118:Calcium
keywords: Ca(2+) mobilization; Chiral agonist; Formyl peptide receptor; Metabolic stability; Neutrophil; Ureidopropanamide