生物活性

• 靶点

  ROCK2 IC50:105nM

  ROCK1 IC50:24μM

• 描述SLx-2119 is a selective ROCK2 inhibitor with IC50 value of 59nM, almost no effect on ROCK1 with Ki value >10μM. SLx-2119 is used in study of cerebrovascular function for it showed brain permeability. Also, it showed anti-adipogenic effects and amelioration of inflammation. At 1h post oral gavage with SLx-2119 at dose of 200mg/kg in mice, the inhibition of ROCK activity in the brain can be observed through decreased level of p-MYPT1-Thr696. Administration of SLx-2119 at dose ranging in 100-300mg/kg dose-dependently reduced infarct volume of mice after transient middle cerebral artery occlusion. A distal middle cerebral artery occlusion model dosed SLx-2119 (200mg/kg) showed improved cortical perfusion, implicating enhanced collateral flow. For SLx-2119 is an ROCK2 selective inhibitor, unlike other ROCK inhibitors, it showed a dose-limiting side effect in acute ischemic stroke such as significant hypotension. In contrast to the pro-adipogenic effect of pan-inhibitors, SLx-2119 (5μM) suppressed adipogenesis in 3T3-L1 cells by regulating key pro-adipogenic factors such as such as PPARγ and C/EBPα in addition to lipogenic factors FABP4 and Glut4, partially through a ROCK2-independent mechanism, making it be a potential anti-adipogenic/obesity agent. Addition of SLx-2119 at concentration of 5 or 10μM into PB-CD4⁺ T cells of IBD patients for 1h subsequently with stimulation with immobilized anti-CD3 and anti-CD28 mAbs for 72h could suppress proinflammatory cytokines, including decreased levels of TNF, IFN-γ, IL-17A, and IL-21 and increased IL-10. Treatment with 10μM SLx-2119 inhibited IBD CD4⁺ T cells to differentiate into Th1 and Th17 cells through downregulating phosphorylated Stat1 and Stat3, but suppressed Treg differentiation through upregulating phosphorylated Stat5 in IBD CD4⁺ T cells.

• 动物研究
  剂量	Mice: 100 mg/ kg - 300 mg/kg[3] (p.o.); 50 mg/kg - 200 mg/kg[2] (i.p.)
  给药途径	p.o., i.p.
  动物药代数据	Animal Mice[3] Dose 100 mg/kg Administration i.g. MRT 6.81 h V 11.58 L T1/2 4.16 h AUCinf 51.93 h·μg/ml Tmax 2 h AUClast 42.31 h·μg/ml CL 1.93 l/h Cmax 7.28 μg/ml

• 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
  NCT02557139	Bioavailability	Phase 1	Completed	-	United Kingdom ... more >> Quotient Clinical Limited Ruddington Nottingham, United Kingdom, NG116JS Collapse <<
  NCT02106195	Psoriasis Vulgaris	Phase 2	Completed	-	United States, California ... more >> UC Irvine Health, Dept of Dermatology Irvine, California, United States, 92697 Collapse <<
  NCT02317627	Psoriasis Vulgaris	Phase 2	Completed	-	United States, Arizona ... more >> Arrowhead Health Centers Glendale, Arizona, United States, 85306 United States, California Southern California Dermatology, Inc. Santa Ana, California, United States, 92701 United States, Louisiana Shondra L. Smith Lake Charles, Louisiana, United States, 70605 United States, Massachusetts Massachusetts General Hospital Boston, Massachusetts, United States, 02114 United States, Nevada Clinical Studies Group, LLC Henderson, Nevada, United States, 89074 United States, New York Icahn School of Medicine at Mount Sinai New York, New York, United States, 10029 United States, North Carolina High Point Clinical Trials Center High Point, North Carolina, United States, 27265 United States, Pennsylvania Altoona Center for Clinical Research Duncansville, Pennsylvania, United States, 16635 United States, Texas Metroplex Clinical Research Center (MCRC) Dallas, Texas, United States, 75231 Collapse <<

• 更多
• 参考文献

• [1] Flynn R, Paz K, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016 Apr 28;127(17):2144-54.

  [2] Zanin-Zhorov A, Weiss JM, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16814-9.

  [3] Lee JH, Zheng Y, et al. Selective ROCK2 Inhibition In Focal Cerebral Ischemia. Ann Clin Transl Neurol. 2014 Jan 1;1(1):2-14.