In vitro activity: PF-4136309 (formerly known as INCB8761) is a novel, potent, selective, and orally available small molecule CCR2 antagonist with IC50 values of 5.2 nM, 17 nM and 13 nM for human, mouse and rat CCR2, respectively. PF-4136309 exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. PF-4136309 has entered human clinical trials. Currently, PF-4136309 has been completed in phase I study for the treatment of pancreatic neoplasms, but no results posted.

Kinase Assay: PF-4136309 is potent in human chemotaxis activity (IC50=3.9 nM) and in the whole blood assay (IC50=19 nM), with IC50 of 16 and 2.8 nM in mouse and rat chemotaxis assays. PF-4136309 is potent in inhibiting CCR2 mediated signaling events such as intracellular calcium mobilization and ERK (extracellular signal-regulated kinase) phosphorylation with IC50 values of 3.3 and 0.5 nM, respectively. In hERG patch clamp assay, PF-4136309 inhibits hERG potassium current with an IC50 of 20 μM. PF-4136309 is not a cytochrome P450 (CYP) inhibitor, with IC50 values of>30 μM against five major CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Moreover, PF-4136309 is not a CYP inducer at concentrations up to 30 μM.

Cell Assay: In vitro ADME (absorption, distribution, metabolism, and excretion) profiling revealed that 17 (PF-4136309) has a moderate permeability across Caco-2 monolayers with a value of 3.1 × 10–6 cm/s. In protein binding, 17had a free fraction of 23% in human serum. When incubated with human liver microsomes, 17 exhibited a moderate intrinsic clearance, with a half-life (t1/2) of 89 min. When 17 was incubated with human S9 with or without NADPH and the cofactor glutathione, no glutathione adducts were detected. Compound 17 is not a cytochrome P450 (CYP) inhibitor, with IC50 values of>30 μM against five major CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Compound 17 is not a CYP inducer at concentrations up to 30 μM.