Uses
CCR4-351 is an orally active, potent and selective CCR4 antagonist. CCR4-351, featuring a novel piperidinyl-azetidine motif, has IC50s of 22 nM and 50 nM in the calcium flux and CTX assay. CCR4-351 has antitumor activity[1].
Biological Activity
CCR4 antagonist 3 is an orally active, potent and selective CCR4 antagonist. CCR4 antagonist 3, featuring a novel piperidinyl-azetidine motif, has IC50s of 22 nM and 50 nM in the calcium flux and CTX assay. CCR4 antagonist 3 has antitumor activity[1].
CCR4 antagonist 3 (compound 38) shows no activity in a CYP450 induction assay[1]. CCR4 antagonist 3 inhibits the migration of mouse iTreg cells with an IC50 of 39 nM, while the IC50 in human iTreg cells is 33 nM[1].
CCR4 antagonist 3 (compound 38; 50 mg/kg; PO; daily; for 40 days) significantly reduces the tumor growth[1]. CCR4 antagonist 3 (0.5 mg/kg; IV) has low clearance (CL=10.2 mL/min/kg), medium volume of distribution (Vss=5.2 L/kg), a T1/2 of 6.9 h, and good bioavailability (%F = 29) of oral dosing in mouse[1]. CCR4 antagonist 3 has low clearance (CL=7.3 mL/min/kg), a half-life of 12.7 hr, and is 44% bioavailable in dog. CCR4 antagonist 3 has low clearance (CL=3.7 mL/min/kg), a long terminal half-life (10.7 hr), and good bioavailability (%F = 41) in cynomolgus monkey[1].
in vivo
CCR4-351 (compound 38; 50 mg/kg; PO; daily; for 40 days) significantly reduces the tumor growth[1].
CCR4-351 (0.5 mg/kg; IV) has low clearance (CL=10.2 mL/min/kg), medium volume of distribution (Vss=5.2 L/kg), a T1/2 of 6.9 h, and good bioavailability (%F = 29) of oral dosing in mouse[1].
CCR4-351 has low clearance (CL=7.3 mL/min/kg), a half-life of 12.7 hr, and is 44% bioavailable in dog. CCR4-351 has low clearance (CL=3.7 mL/min/kg), a long terminal half-life (10.7 hr), and good bioavailability (%F = 41) in cynomolgus monkey[1].
| Animal Model: | Six-to eight-week-old, female C57BL/6 mice with Pan02-OVA tumor[1] |
| Dosage: | 50 mg/kg |
| Administration: | PO; daily; for 40 days |
| Result: | Significantly reduced the tumor growth.
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| Animal Model: | Rat and mouse[1] |
| Dosage: | 0.5 mg/kg of IV; 2 mg/kg of PO |
| Administration: | IV or PO |
| Result: | Possessed medium clearance (CL=47.6 mL/min/kg) and was 49% bioavailable upon oral dosing in rat.
Had low clearance (CL=10.2 mL/min/kg), medium volume of distribution (Vss=5.2 L/kg), a T1/2 of 6.9 h, and good bioavailability (%F = 29) of oral dosing in mouse.
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References
[1]. Omar Robles, et al. Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as Single Agent and in Combination with Checkpoint Inhibitors. J Med Chem. 2020 Jul 15.
![1H-Pyrazolo[3,4-b]pyrazine-3-carbonitrile, 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[3-[(3R)-1-(2-hydroxyethyl)-3-piperidinyl]-1-azetidinyl]- Structure](https://www.chemicalbook.com/CAS/20210305/GIF/2174938-70-4.gif)