CXCR3 inhibitors for therapeutic interventions: current status and perspectives

Abstract

CXC chemokine receptor 3 (CXCR3) is a G protein-coupled chemokine receptor that plays a key role in regulating immune responses and is involved in various pathological processes, particularly in tumor development and inflammatory diseases, making it a novel target for clinical therapy. The expression of CXCR3 and its ligands-CXCL9, CXCL10, CXCL11, CXCL4, and CXCL4L1-is closely associated with the onset and progression of numerous diseases. With a deeper understanding of the mechanisms underlying CXCR3 function, significant progress has been made in the development of small molecule antagonists targeting CXCR3, some of which have entered clinical trials and demonstrated therapeutic potential. This review provides an overview of the structure and signaling pathways of CXCR3, its biological functions in cancer and inflammatory diseases, and highlights the innovative roles of CXCR3 in these diseases. Furthermore, it discusses recent advances in the development of small molecule antagonists, particularly those that have been tested in clinical settings, such as AMG 487 and ACT-777991. These studies provide a scientific foundation for the development of novel CXCR3 antagonists and may offer new directions for future clinical treatments.

Keywords: CXCR3; CXCR3 inhibitors; future clinical treatments; inflammatory diseases,; molecule antagonists,; tumor.

FIGURE 1

Structures of CXCR3 gene and three subtypes.

FIGURE 2

CXCR3 signal pathways.

FIGURE 3

Relationship between CXCR3 and various diseases. RA, rheumatoid arthritis; IBD, inflammatory bowel diseases; COPD, chronic obstructive pulmonary diseases; MS, multiple sclerosis; AD, alzheimer’s diseases.

FIGURE 4

Structures and Optimization Pathways of Piperazine-based Piperidine Compounds. (A) Structure and optimization of piperazine-based piperidine compounds. For compound 3, the chloro-benzyl group is a key moiety for enhancing the compound’s affinity. While shortening the N-benzylamide group decreases its affinity, introducing small alkyl groups, particularly (S)-substituents on the piperazine ring, significantly improves its in vitro activity. Halogenation of the benzamide group in compound 4 strengthens its binding affinity to CXCR3, and substituting the amide group with heterocyclic moieties increases its oral bioavailability. (B) Structure and optimization of arylpiperazine compounds. Compounds 7 and 8 contain amide or aryl groups at the ortho position of homopiperazine, which is crucial for maintaining their activity. SAR studies of compound 9 indicate that the central phenyl ring can accommodate a third substituent, such as an amide group, similar to compounds studied by Ligand Pharmaceuticals, or a halogen atom, and can also be modified to include a pyridine ring. The central phenyl ring of compound 10 can tolerate additional substituents, such as halogens or amide groups, which provide opportunities to fine-tune the pharmacological properties of the compound.

FIGURE 5

Structures and Optimization Pathways of 8-Azaquinazolinone Compounds.

FIGURE 6

Structures and optimization pathways of aryl sulfonamide compounds, spiropiperidine compounds, benzimidazole derivatives, phenylethylpiperidine derivatives, and 1-phenyl-3-piperidin-4-ylurea derivatives. (A) Structure and optimization of aryl sulfonamide compounds. Replacing the acetohydrazone structure of compound 23 with an amide does not affect its CXCR3 antagonistic activity. In the design of compound 25, a diversity exploration was conducted on the amide N-substituent R3, revealing a preference for more hydrophobic groups, particularly thiophene methylene and 1-phenyl-cycloprop-1-yl groups. Additionally, compound 25 contains a crucial chlorine atom at the R1 position on the sulfonamide ring, which is essential for maintaining the activity of the compound. Furthermore, a second benzyl substituent R2 on the sulfonamide nitrogen also shows some tolerance, with a preference for aromatic or heteroaromatic groups containing an unsubstituted methylene chain, especially the 2-pyridyl group. (B) Spiropiperidine compound structure. The different cyclic structures on the piperidine ring of compound 26 may be related to its potential binding to the CXCR3 receptor. (C) Structure and optimization of benzimidazole compounds. SAR studies show that the small aliphatic substituent at the C-4 position of compound 27 enhances its potency, leading to the discovery of compound 28. (D) Structure and optimization of phenylethylpiperidine derivatives. (E) Structure and optimization of 1-phenyl-3-piperidin-4-ylurea derivatives. For compound 34, acylated piperidine exhibits superior CXCR3 activity compared to the corresponding piperidine.

FIGURE 7

Structures and Optimization Pathways of Non-Specific Antagonists and Natural Products. (A) Quaternary Ammonium Salt Derivatives: The binding site of compound 36 to CXCR3 differs from that of another antagonist, VUF10085, in that it does not rely on the key amino acid residues that are essential for VUF10085 binding. (B) Camphor Sulfonamide Compounds: The structure and optimization of camphor sulfonamide derivatives. Compound 38 was discovered by systematically modifying the phenyl ring, piperidine ring, and camphor bicyclic structure of compound 37, incorporating optimal substituents. (C) Benzimidazole Derivatives: Structure and optimization of benzimidazole-based CXCR3 antagonists. (D-E) Natural Products: Structure and optimization pathway of natural products. For compound 42, replacing the N,N-diethylamide group with a pyrrolidinamide resulted in a tenfold increase in activity. Introducing hydrophobic substituents on the indole nitrogen of compound 42 led to reduced activity, while incorporating polar substituents not only maintained activity in binding and cell assays but also enhanced activity in whole blood experiments.