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Selective and Dual Targeting of CCR2 and CCR5 Receptors: A Current Overview

The chemokine receptor 2 (CCR2) and chemokine receptor 5 (CCR5) are important mediators of leukocyte trafficking in inflammatory processes. The emerging evidence for a role of CCR2 and CCR5 receptors in human inflammatory diseases led to a growing interest in CCR2- and CCR5-selective antagonists. In...

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Detalles Bibliográficos
Autores principales: Junker, Anna, Kokornaczyk, Artur Kamil, Strunz, Ann Kathrin, Wünsch, Bernhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123309/
http://dx.doi.org/10.1007/7355_2014_40
Descripción
Sumario:The chemokine receptor 2 (CCR2) and chemokine receptor 5 (CCR5) are important mediators of leukocyte trafficking in inflammatory processes. The emerging evidence for a role of CCR2 and CCR5 receptors in human inflammatory diseases led to a growing interest in CCR2- and CCR5-selective antagonists. In this review, we focus on the recent development of selective CCR2/CCR5 receptor ligands and dual antagonists. Several compounds targeting CCR2, e.g., INCB8761 and MK0812, were developed as promising candidates for clinical trials, but failed to show clinical efficacy as presumed from preclinical models. The role of CCR5 receptors as the second co-receptor for the HIV-host cell fusion led to the development of various CCR5-selective ligands. Maraviroc is the first CCR5-targeting drug for the treatment of HIV-1 infections on the market. The role of CCR5 receptors in the progression of inflammatory processes fueled the use of CCR5 antagonists for the treatment of rheumatoid arthritis. Unfortunately, the use of maraviroc for the treatment of rheumatoid arthritis failed due to its inefficacy. Some of the ligands, e.g., TAK-779 and TAK-652, were also found to be dual antagonists of CCR2 and CCR5 receptors. The fact that CCR2 and CCR5 receptor antagonists contribute to the treatment of inflammatory diseases renders the development of dual antagonists as promising novel therapeutic strategy.