生物活性

• 描述PF-4136309 is a potent and selective CCR2 antagonist with weak hERG activity (IC50 of 20 μM in hERG patch clamp assay) and excellent in vitro and in vivo profile of absorption, distribution, metabolism, excretion and toxicology. PF-4136309 exhibited CCR2 binding affinity with IC50 value of 5.2nM and chemotaxis activity with IC50 value of 3.9nM. PF-4136309 potently inhibited CCR2 mediated signaling events such as intracellular calcium mobilization and p-ERK with IC50 values of 3.3 and 0.5 nM, respectively. PF-4136309 is also a potent murine CCR2 antagonist with IC50 values of 17 and 13 nM in mouse and rat binding assays and 16 and 2.8 nM in mouse and rat chemotaxis assays. Oral administration of PF-4136309 at dose of 2mg/kg achieved bioavailability of 78% in dog and rat.

• 动物研究
  剂量	Rat: 2 mg/kg[1] (i.v.); 10 mg/kg[1] (p.o.) Dog: 2 mg/kg[1] (i.v.); 10 mg/kg[1] (p.o.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Rats[1] Dogs[1] Dose 2 mg/kg (i.v.) 10 mg/kg (p.o.) 2 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 78% (p.o.) 78% (p.o.) T1/2 2.5 h (i.v.) 2.5 h (p.o.) 2.4 h (i.v.) 3.2 h (p.o.) Tmax 1.2 h (p.o.) 0.25 h (p.o.) CL 1.41 l/h/kg (i.v.) 0.46 l/h/kg (i.v.) Cmax 610 nM (p.o.) 20039 nM (p.o.) Vss 7.0 l/kg (i.v.) 0.62 l/kg (i.v.) AUC 2723 nM·h (p.o.) 35560 nM·h (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01413022	Pancreatic Neoplasms	Phase 1	Completed	-	United States, Missouri ... more >> Washington University School of Medicine Saint Louis, Missouri, United States, 63110 Collapse <<
  NCT01226797	Hepatitis C, Chronic	Phase 2	Terminated(See termination rea... more >>son in detailed description.) Collapse <<	-	Hong Kong ... more >> Pfizer Investigational Site Hong KOng, Hong Kong, 0 Pfizer Investigational Site Prince of Wales Hospital, Shatin, New Territories,, Hong Kong, 0 India Pfizer Investigational Site Bangalore, Karnataka, India, 560017 Pfizer Investigational Site Mumbai, Maharashtra, India, 400 012 Pfizer Investigational Site New Delhi, India, 110 070 Korea, Republic of Pfizer Investigational Site Seoul, Korea, Republic of, 110-744 Pfizer Investigational Site Seoul, Korea, Republic of, 120-752 Singapore Pfizer Investigational Site Singapore, Singapore, 169608 Taiwan Pfizer Investigational Site Kaohsiung, Taiwan, 807 Pfizer Investigational Site Taipei, Taiwan, 100 Collapse <<

• 参考文献

• [1] Xue CB, Wang A, et al. Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist. ACS Med Chem Lett. 2011 Oct 5;2(12):913-8.