DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain

Author(s):Show less -

Lopes, Alexandre H. ^{[1, 2]} ; Brandolini, Laura ^{[1, 3]} ; Aramini, Andrea ^{[1, 3]} ; Bianchini, Gianluca ^{[1, 3]} ; Silva, Rangel L. ^{[1, 2]} ; Zaperlon, Ana C. ^{[4, 1]} ; Verri, Jr., Waldiceu A. ^{[4, 1]} ; Alves-Filho, Jose C. ^{[1, 2]} ; Cunha, Fernando Q. ^{[1, 2]} ; Teixeira, Mauro M. ^{[4, 1]} ; Allegretti, Marcello ^{[1, 3]} ; Cunha, Thiago M. ^{[1, 2]}

Affiliation

^[1] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Immunol, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Dompe Farmaceut Spa, R&D Dept, Via Campo di Pile, I-67100 Laquila - Italy

^[4] Univ Estadual Londrina, Dept Patol, Ctr Ciencias Biol, Rod Celso Garcia Cid PR445 KM380, BR-86051990 Londrina, Parana - Brazil

• Document type: Journal article
• Source: PHARMACOLOGICAL RESEARCH; v. 103, p. 69-79, JAN 2016.
• Web of Science Citations: 7

Abstract

The activation of CXCR1/2 has been implicated in the genesis of inflammatory and postoperative pain. Here, we investigated a novel orally acting allosteric inhibitor of CXCR1/2 (DF2755A) and evaluated its antinociceptive effect in several models of inflammatory and post-operatory pain. DF2755A was tested in vitro for efficacy in the chemotaxis assay, selectivity and toxicity. In vivo, C57B1/6 mice were treated orally with DF2755A and the following experiments were performed: pharmacokinetic profile; inflammatory hyperalgesia models using electronic pressure meter test; neutrophil migration assay assessed by myeloperoxidase assay. DF2755A selectively inhibited neutrophil chemotaxis induced by CXCR1/2 ligands without effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF2755A on CXCL8-induced chemotaxis. DF2755A given orally was well absorbed (88.2%), and it was able to reduce, in a dose (3-30 mg/kg)-dependent manner, inflammatory hyperalgesia induced by carrageenan, LPS and CXCL1/KC as well as neutrophil recruitment and IL-1 beta production. In addition, DF2755A was able to reduce post-incisional nociception. Therapeutic treatment with DF2755A reduced CFA-induced inflammatory hyperalgesia even when injected intrathecally. The present results indicate that DF2755A is a novel selective allosteric inhibitor of CXCR1/2 with a favorable oral pharmacokinetic profile. Furthermore, the results might suggest that DF2755A might be a candidate of a novel therapeutic option to control inflammatory and post-operative pain. (C) 2015 Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Projects - Thematic Grants