Characterization of CCX282-B, an Orally Bioavailable Antagonist of the CCR9 Chemokine Receptor, for Treatment of Inflammatory Bowel Disease (original) (raw)

Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

, Yu Wang, Nu Lai, Trageen Baumgart, Bin N. Zhao, Daniel J. Dairaghi, Pirow Bekker, Linda S. Ertl, Mark E. T. Penfold, Juan C. Jaen, Satish Keshav, Emily Wendt, Andrew Pennell, Solomon Ungashe, Zheng Wei, J. J. Kim Wright and Thomas J. Schall

Journal of Pharmacology and Experimental Therapeutics October 2010, 335 (1) 61-69; DOI: https://doi.org/10.1124/jpet.110.169714

Abstract

The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca2+ mobilization and chemotaxis on Molt-4 cells with IC50 values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC50 of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC50 of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC50 values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNFΔARE mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.

Footnotes

• Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
  doi:10.1124/jpet.110.169714.

• ↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

• ABBREVIATIONS:
  CCR9
  chemokine receptor 9
  CCL25
  chemokine ligand 25
  IBD
  inflammatory bowel disease
  MLN
  mesenteric lymph nodes
  IL
  interleukin
  TNF
  tumor necrosis factor
  PCR
  polymerase chain reaction
  PBMC
  peripheral blood mononuclear cell
  HBSS
  Hank's balanced salt solution
  BSA
  bovine serum albumin
  DMSO
  dimethyl sulfoxide
  RA
  retinoic acid
  ARE
  AU-rich
  AAG
  α1-acid glycoprotein.

• Received May 4, 2010.

• Accepted July 20, 2010.

• Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics

View Full Text

Log in using your username and password

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.