2. Academic Validation
  3. Phenylpyridine-2-ylguanidines and rigid mimetics as novel inhibitors of TNFα overproduction: Beneficial action in models of neuropathic pain and of acute lung inflammation

Phenylpyridine-2-ylguanidines and rigid mimetics as novel inhibitors of TNFα overproduction: Beneficial action in models of neuropathic pain and of acute lung inflammation

  • Eur J Med Chem. 2018 Mar 10:147:163-182. doi: 10.1016/j.ejmech.2018.01.049.
Maud Bollenbach 1,  Eric Salvat 2,  François Daubeuf 3,  Patrick Wagner 1,  Ipek Yalcin 4,  Muris Humo 4,  Baptiste Letellier 4,  Léa J Becker 4,  Frédéric Bihel 1,  Jean-Jacques Bourguignon 1,  Pascal Villa 5,  Adeline Obrecht 5,  Nelly Frossard 1,  Michel Barrot 4,  Martine Schmitt 6
Affiliations

Affiliations

  • 1 CNRS, Université de Strasbourg, UMR7200 Laboratoire d' Innovation Thérapeutique, 67401 Illkirch, France; Labex MEDALIS, 67000 Strasbourg, France.
  • 2 CNRS, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France; Hôpitaux universitaires de Strasbourg, Centre d'Evaluation et de Traitement de la Douleur, 67000 Strasbourg, France.
  • 3 CNRS, Université de Strasbourg, UMR7200 Laboratoire d' Innovation Thérapeutique, 67401 Illkirch, France; CNRS, Université de Strasbourg, UMS3286 PCBIS Plateforme de chimie biologique intégrative, 67400 Illkirch, France; Labex MEDALIS, 67000 Strasbourg, France.
  • 4 CNRS, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France.
  • 5 CNRS, Université de Strasbourg, UMS3286 PCBIS Plateforme de chimie biologique intégrative, 67400 Illkirch, France; Labex MEDALIS, 67000 Strasbourg, France.
  • 6 CNRS, Université de Strasbourg, UMR7200 Laboratoire d' Innovation Thérapeutique, 67401 Illkirch, France; Labex MEDALIS, 67000 Strasbourg, France. Electronic address: mschmitt@unistra.fr.
PMID: 29432948 DOI: 10.1016/j.ejmech.2018.01.049
Abstract

4-phenylpyridin-2-yl-guanidine (5b): a new inhibitor of the overproduction of pro-inflammatory cytokines (TNFα and Il1β) was identified from a high-throughput screening of a chemical library on human peripheral blood mononuclear cells (PBMCs) after LPS stimulation. Derivatives, homologues and rigid mimetics of 5b were designed and synthesized, and their cytotoxicity and ability to inhibit TNFα overproduction were evaluated. Among them, compound 5b and its mimetic 12 (2-aminodihydroquinazoline) showed similar inhibitory activities, and were evaluated in vivo in models of lung inflammation and neuropathic pain in mice. In particular, compound 12 proved to be active (5 mg/kg, IP) in both models.

Keywords

Inflammation; Neuropathic pain; Phenotypic screening; Pyridine-2-yl guanidine; TNFα inhibitor.

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