Lacivita Enza, Schepetkin Igor A, Stama Madia L, Kirpotina Liliya N, Colabufo Nicola A, Perrone Roberto, Khlebnikov Andrei I, Quinn Mark T, Leopoldo Marcello
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy.
Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
Bioorg Med Chem. 2015 Jul 15;23(14):3913-24. doi: 10.1016/j.bmc.2014.12.007. Epub 2014 Dec 13.
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.
N-甲酰基肽受体（FPRs）是G蛋白偶联受体（GPCRs），在炎症反应中起关键作用，FPR特异性相互作用可能有助于解决病理性炎症反应。我们在此报告了六对手性脲基丙酰胺衍生物的合成及生物学评价，这些衍生物是从我们的先导激动剂（S）-3-（1H-吲哚-3-基）-2-[3-（4-甲氧基苯基）脲基]-N-[[1-（5-甲氧基-2-吡啶基）环己基]甲基]丙酰胺（（S）-9a）开始设计的强效且选择性的甲酰基肽受体-2（FPR2）激动剂。新化合物的总收率明显高于（S）-9a。几种新化合物显示出与（S）-9a相当的激动剂特性，并且对FPR1具有更高的选择性。分子建模用于确定FPR2的手性识别。还评估了所选化合物的体外代谢稳定性，以初步了解这类化合物的类药物性质。
