2. Academic Validation
  3. Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia

Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia

  • J Med Chem. 2018 Sep 13;61(17):7671-7686. doi: 10.1021/acs.jmedchem.8b00657.
Pierre Regenass 1 2,  Dayana Abboud 3 2,  François Daubeuf 1 4 2,  Christine Lehalle 1 4 2,  Patrick Gizzi 4 2,  Stéphanie Riché 1 2,  Muriel Hachet-Haas 3 2,  François Rohmer 1 2,  Vincent Gasparik 1 2,  Damien Boeglin 1 2,  Jacques Haiech 1 2,  Tim Knehans 1 2,  Didier Rognan 1 2,  Denis Heissler 1 2,  Claire Marsol 1 4 2,  Pascal Villa 4 2,  Jean-Luc Galzi 3 2,  Marcel Hibert 1 2,  Nelly Frossard 1 2,  Dominique Bonnet 1 2
Affiliations

Affiliations

  • 1 Laboratoire d'Innovation Thérapeutique , Faculté de Pharmacie, UMR7200 CNRS/Université de Strasbourg , 74 route du Rhin , 67401 Illkirch , France.
  • 2 Labex MEDALIS , Université de Strasbourg , 67000 Strasbourg , France.
  • 3 Biotechnologie et Signalisation Cellulaire , Ecole Supérieure de Biotechnologie de Strasbourg, UMR 7242 CNRS/Université de Strasbourg , Bld Sébastien Brant , 67412 Illkirch , France.
  • 4 Plate-forme de chimie biologique intégrative de Strasbourg , UMS 3286 CNRS/Université de Strasbourg , 67412 Illkirch , France.
PMID: 30106292 DOI: 10.1021/acs.jmedchem.8b00657
Abstract

We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor. While both 1 and 57 reduce eosinophil recruitment in a murine model of allergic airway hypereosinophilia, 57 is the only one to display inhibitory activity following oral administration. Thereby, we here describe 57 as the first orally active CXCL12 neutraligand with anti-inflammatory properties. Combined with a high binding selectivity for CXCL12 over Other chemokines, 57 represents a powerful pharmacological tool to investigate CXCL12 physiology in vivo and to explore the activity of chemokine neutralization in inflammatory and related diseases.

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