C-021

C-021 is a potent CC chemokine receptor-4 (CCR4) antagonist. C-021 potently inhibits functional chemotaxis in human and mouse with IC50s of 140 nM and 39 nM, respectively. C-021 effectively prevents human CCL22-derived [35S]GTPγS from binding to the receptor with an IC50 of 18 nM[1].

Signaling Pathways >> GPCR/G Protein >> CCR

Signaling Pathways >> Immunology/Inflammation >> CCR

Research Areas >> Inflammation/Immunology

CCR4

The in vitro oxidative metabolic stability of C-021 (Compound 1b) is evaluated by measuring the rate of drug consumption in human liver microsomes (HML), thus providing intrinsic clearance values (CLint). C-021 exhibits CLint value of 17,377 mL/h/kg[1].

The potency of C-021 (Compound 1b) is evident after subcutaneous administration in the murine oxazolone-induced contact hypersensitivity test, a known model of acute skin inflammation. When C-021 is administered orally, however, very little inhibition is observed[1]. C-021 (1 mg/kg; i.p.; daily; for 3 days) significantly less microgliosis in acute liver failuremice[2]. Animal Model: Male C57Bl/6 mice (20-25 g) with acute liver failure[2] Dosage: 1 mg/kg Administration: i.p.; daily; for 3 days Result: Significantly less microgliosis, and significantly reduced the pERK1/2 to tERK1/2 ratio.

[1]. Yokoyama K, et al. Potent and orally bioavailable CCR4 antagonists: Synthesis and structure-activity relationship study of 2-aminoquinazolines. Bioorg Med Chem. 2009 Jan 1;17(1):64-73.

[2]. Matthew McMillin, et al. Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline. J Neuroinflammation. 2014 Jul 10;11:121.