生物活性

• 描述Autotaxin (ATX) is an ectoenzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive lipid and a close relative of sphingosine 1-phosphate. High endothelial venules (HEVs) produce and secrete ATX into the blood. HA130 is a selective ATX inhibitor with an IC₅₀ of 28 nM. HA130 abolished the enhancing effect of ATX on TEM (transendothelial migration) and HA130 at 0.3 mM completely ablated the activity of ATX on TK1 uropod formation. When injecting CFSE-labeled T cells together with HA130 i.v. into mice and then reinjecting the drug at 7 and 12 min, SLOs (secondary lymphoid organs) were sectioned and stained to reveal HEVs after 15 min. The ratio of outside HEVs to inside HEVs was used as an index of T cell migration across HEVs. HA130 decreased the outside HEV/inside HEV ratio by 3–4-fold compared with vehicle treatment (p＜0.01 for both PLNs (peripheral lymph node) and MLNs (mesenteric lymph node)). This result is consistent with HA130 retarding the migration of T cells across LN (lymph node) HEVs. The s.c. administration of HA130 induces marked lymphocyte accumulation within the endothelial cell (EC) and sub-EC layers of HEVs in draining lymph nodes.
• 作用机制π−π stacking interactions and a bidentate hydrogen-bonding interaction in the pyridazinone moiety were observed, and the N2 nitrogen atom of the pyrazole ring formed a water-mediated interaction with OH of Tyr514 as well.
• 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
  NCT01879722	Schizophrenia	Phase 1	Completed	-	United States, California ... more >> Glendale, California, United States Collapse <<
  NCT01879722	-	-	Completed	-	-
  NCT02477020	Schizophrenia	Phase 2	Completed	-	United States, Alaska ... more >> Springdale, Alaska, United States United States, California Culver City, California, United States Lemon Grove, California, United States Long Beach, California, United States Pico Rivera, California, United States United States, Florida Lauderhill, Florida, United States Orlando, Florida, United States United States, Georgia Atlanta, Georgia, United States United States, Louisiana Lake Charles, Louisiana, United States United States, Missouri Saint Louis, Missouri, United States United States, Nevada Las Vegas, Nevada, United States United States, Oklahoma Oklahoma City, Oklahoma, United States United States, Texas Austin, Texas, United States Dallas, Texas, United States Houston, Texas, United States Collapse <<

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• 参考文献

• [1] Kunitomo J, Yoshikawa M, et al. Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl] -5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor. J Med Chem. 2014 Nov 26;57(22):9627-43.

  [2] Suzuki K, Harada A, et al. In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents. J Pharmacol Exp Ther. 2015 Mar;352(3):471-9.