Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2) Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders.

Autor: Mastromarino M; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy., Favia M; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy., Schepetkin IA; Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana 59717, United States., Kirpotina LN; Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana 59717, United States., Trojan E; Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smȩtna St., 31-343 Kraków, Poland., Niso M; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy., Carrieri A; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy., Leśkiewicz M; Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smȩtna St., 31-343 Kraków, Poland., Regulska M; Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smȩtna St., 31-343 Kraków, Poland., Darida M; Aptuit Srl, an Evotec Company, Via A. Fleming, 4, 37135 Verona, Italy., Rossignolo F; Aptuit Srl, an Evotec Company, Via A. Fleming, 4, 37135 Verona, Italy., Fontana S; Aptuit Srl, an Evotec Company, Via A. Fleming, 4, 37135 Verona, Italy., Quinn MT; Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana 59717, United States., Basta-Kaim A; Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smȩtna St., 31-343 Kraków, Poland., Leopoldo M; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy., Lacivita E; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Mar 24; Vol. 65 (6), pp. 5004-5028. Date of Electronic Publication: 2022 Mar 08.
DOI: 10.1021/acs.jmedchem.1c02203
Abstrakt: Formyl peptide receptor 2 (FPR2) agonists can boost the resolution of inflammation and can offer alternative approaches for the treatment of pathologies with underlying chronic neuroinflammation, including neurodegenerative disorders. Starting from the FPR2 agonist 2 previously identified in our laboratory and through fine-tuning of FPR2 potency and metabolic stability, we have identified a new series of ureidopropanamide derivatives endowed with a balanced combination of such properties. Computational studies provided insights into the key interactions of the new compounds for FPR2 activation. In mouse microglial N9 cells and in rat primary microglial cells stimulated with lipopolysaccharide, selected compounds inhibited the production of pro-inflammatory cytokines, counterbalanced the changes in mitochondrial function, and inhibited caspase-3 activity. Among the new agonists, ( S )- 11l stands out also for the ability to permeate the blood-brain barrier and to accumulate in the mouse brain in vivo , thus representing a valuable pharmacological tool for studies in vivo .
Databáze: MEDLINE
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