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

Pierre Regenass; Dayana Abboud; François Daubeuf; Christine Lehalle; Patrick Gizzi; Stéphanie Riché; Muriel Hachet-Haas; François Rohmer; Vincent Gasparik; Damien Boeglin; Jacques Haiech; Tim Knehans; Didier Rognan; Denis Heissler; Claire Marsol; Pascal Villa; Jean-Luc Galzi; Marcel Hibert; Nelly Frossard; Dominique Bonnet

doi:10.1021/acs.jmedchem.8b00657

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. Epub 2018 Aug 28.

Authors

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

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
Anti-Inflammatory Agents, Non-Steroidal / chemistry*
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Chemokine CXCL12 / chemistry
Chemokine CXCL12 / metabolism*
Disease Models, Animal
Drug Evaluation, Preclinical
Fluorescence Resonance Energy Transfer
Humans
Hypereosinophilic Syndrome / drug therapy*
Hypersensitivity / drug therapy
Hypersensitivity / etiology
Male
Mice, Inbred BALB C
Models, Molecular
Pyrimidinones / administration & dosage
Pyrimidinones / chemistry*
Pyrimidinones / metabolism
Pyrimidinones / pharmacokinetics
Pyrimidinones / pharmacology*
Receptors, CXCR4 / genetics
Receptors, CXCR4 / metabolism
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
CXCR4 protein, human
Chemokine CXCL12
LIT-927
Pyrimidinones
Receptors, CXCR4