CCR4 antagonist 3 is an orally active, potent and selective CCR4 antagonist. CCR4 antagonist 3, featuring a novel piperidinyl-azetidine motif, has IC 50 s of 22 nM and 50 nM in the calcium flux and CTX assay. CCR4 antagonist 3 has antitumor activity.

CCR4 antagonist 3 (compound 38) shows no activity in a CYP450 induction assay[1]. CCR4 antagonist 3 inhibits the migration of mouse iT reg cells with an IC 50 of 39 nM, while the IC 50 in human iT reg cells is 33 nM[1].

CCR4 antagonist 3 demonstrated significant anti-tumor activity in a mouse model of Pan02-OVA tumors, administered as a 50 mg/kg oral dose daily for 40 days, resulting in a notable reduction in tumor growth. Pharmacokinetic profiles across species revealed that CCR4 antagonist 3, at a dosage of 0.5 mg/kg intravenously, exhibits low clearance (CL=10.2 mL/min/kg) and medium volume of distribution (Vss=5.2 L/kg) with a half-life (T 1/2) of 6.9 hours and 29% bioavailability in mice. In dogs, it showed a clearance of 7.3 mL/min/kg, a half-life of 12.7 hours, and 44% bioavailability. Cynomolgus monkeys demonstrated a clearance of 3.7 mL/min/kg, a long half-life of 10.7 hours, and 41% bioavailability. Additionally, when administered orally at 2 mg/kg in rats and 0.5 mg/kg intravenously or orally in mice, the compound achieved medium clearance (CL=47.6 mL/min/kg) with 49% bioavailability in rats and maintained its pharmacokinetic profile of low clearance, medium volume of distribution, a 6.9-hour half-life, and 29% bioavailability in mice.