CXCR7modulator2是CXCR7的调节剂，其Ki值为13nM。
CXCR7 modulator 2 is a modulator of C-X-C Chemokine Receptor Type 7 (CXCR7), with a Ki of 13 nM.
CXCR7 modulator 2 (compound 18) demonstrates potent CXCR7-binding affinity (Ki=13 nM) and β-arrestin activity (EC50=11 nM). CXCR7 modulator 2 also exhibits improved selectivity in the GPCR panel and an improved therapeutic index in the hERG patch-clamp assay in comparison with 11c. CXCR7 modulator 2 exhibits moderate to high in vitro turn over in both NADPH-supplemented mouse-liver microsomes (MLM, 93 μL/min/mg) and hepatocytes (28 μL/min per million cells), shows poor passive absorptive permeability in the MDCK II-permeability assay, and has good aqueous solubility. CXCR7 modulator 2 is rapidly absorbed with a mean maximal plasma concentration (Cmax) of 682 ng/mL, which occurrs at 0.25 h (Tmax). The corresponding mean area under the plasma-concentration-versus-time profile (AUC) is 740 ng/mL/h[1].
The administration of isoproterenol for 9 days leads to the development of cardiac fibrosis, as attested by the approximately 4-fold increase in collagen deposition relative to that in the control, which is detected by picrosirius-red staining. Treatment with CXCR7 modulator 2 results in a statistically significant reduction in cardiac fibrosis, thereby demonstrating the protective role of CXCR7 modulation with CXCR7 modulator 2 in an isoproterenol-induced cardiac injury[1].
[1]. Menhaji-Klotz E, et al. Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis. J Med Chem. 2018 Apr 26;61(8):3685-3696.
Cell experiment: | Measurements of potassium currents in HEK293 cells are stably transfected with the hERG channel[1]. |
Animal experiment: | Mice[1]A total of 60 male BALB/c mice (8 weeks of age) are randomized into four study groups. In two groups, isoproterenol (5 mg/kg) is administered subcutaneously once daily for 9 days to induce cardiac fibrosis. In addition, the mice in these two groups are further treated twice daily throughout the 9 day study duration with either CXCR7 modulator 2 at 30 mg/kg (n=20) or the vehicle (n=20). The mice in the third group receives PBS and the vehicle and thus serves as controls (n=15). The fourth group (n=5), which receives both isoproterenol and CXCR7 modulator 2, are used for blood sampling at 1 and 9 h postdose on days 1, 3, 6, and 9 (1 h only) to provide an overall estimate of CXCR7 coverage relative to mouse Ki. The exposures to CXCR7 modulator 2 achieved in the BALB/c mice at the 30 mg/kg dose are approximately as expected, with the unbound Cave>95% target coverage[1]. |
参考文献: [1]. Menhaji-Klotz E, et al. Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis. J Med Chem. 2018 Apr 26;61(8):3685-3696. | |
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