CCR4 antagonist 3 hydrochloride

CCR4 antagonist 3 hydrochloride 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].

Signaling Pathways >> GPCR/G Protein >> CCR

Research Areas >> Cancer

Signaling Pathways >> Immunology/Inflammation >> CCR

Research Areas >> Metabolic Disease

CCR4

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]. 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. 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.

[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.