CCR1 and CCR2 Antagonists

Abstract

Chemokines constitute a family of small heparin-binding proteins which orchestrate the infiltration of leukocytes during inflammation, but also directly influence other physiological and pathophysiological processes. In humans, more than 40 chemokines are known binding to around 18 G-protein-coupled receptors. A non-redundant role of certain chemokines and their receptors has been identified within the last years in inflammation and host defense. Among chemokine receptors, the CC chemokine receptors CCR1 and CCR2 have been shown to play a crucial role in these processes. Importantly, these receptors have already been targeted by specific antagonists in early human trials for autoimmune and infectious diseases. Although most of these antagonists failed to show any significant efficacy in the clinic, the knowledge of their biological effects could henceforth offer new avenues with optimal strategies for producing successful therapeutics.

A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer

“…Due to its involvement in various biological and pathological functions, CCR2 is an attractive target for drug discovery. However, development of CCR2 antagonists has been disappointing because of receptor redundancy, species differences, selectivity of other chemokine receptors, and limited clinical efficacy ( Zimmermann et al, 2014 ). Since none of the present CCR2 antagonists has passed clinical trials, new concepts and strategies are needed.…”

“…CCR2 antagonists have been developed and evaluated in pre-clinical and clinical trials mainly due to the need for eliminating monocytes/macrophages, which would ameliorate inflammation associated with diseases. Although various agents have been discovered, and several have entered clinical trials, none have proved effective due to the selectivity of other chemokine receptors, their lack of potency in binding to rodent receptors, and poor PK/PD profiles ( Struthers and Pasternak, 2010 , Zimmermann et al, 2014 ).…”

Can we target CCR2 to treat osteoarthritis? The trick is in the timing!

“…Signaling through CCR2 has been implicated in many pathologies, including autoimmune disorders, tumor metastasis, atherosclerosis, stroke, neurodegenerative disorders, and neurological complications of HIV [2]. As a GPCR, CCR2 is eminently druggable and many small-molecule antagonists have been tested in clinical trials for different conditions [2, 3]. …”

“…As the main chemotactic pathway for monocytes, the CCL2/CCR2 axis is key for recruitment of CCR2-expressing circulating monocytes to sites of inflammation [3]. In addition, CCR2 is expressed by other immune cells such as CD4+ T H 1 cells [3].…”

“…As the main chemotactic pathway for monocytes, the CCL2/CCR2 axis is key for recruitment of CCR2-expressing circulating monocytes to sites of inflammation [3]. In addition, CCR2 is expressed by other immune cells such as CD4+ T H 1 cells [3]. Even though osteoarthritis (OA) is not considered a primarily inflammatory process, there is an increasing awareness that innate immune pathways and chronic low-grade inflammation may critically contribute to the pathogenesis of OA.…”