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.
体内研究
Balipodect (TAK-063) exhibits outstanding selectivity (>15000-fold selectivity over other PDEs) and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of Balipodect (TAK-063) at 0.3 mg/kg to mice increased striatal 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels, and demonstrated potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg [1].
Balipodect (TAK-063) administered orally at doses of 0.3 and 1 mg/kg increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP-dependent and cGMP-dependent protein kinases. It also effectively suppressed MK-801-induced hyperlocomotion, a commonly used predictive model for antipsychotic-like activity in rodents. Balipodect (TAK-063) did not alter plasma prolactin or glucose levels at doses up to 3 mg/kg (pO.). However, at a dose of 3 mg/kg orally, Balipodect (TAK-063) induced a mild cataleptic response compared to haloperidol and olanzapine [2].
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.
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