LP-935509

LP-935509 is an orally active, potent, selective, ATP-competitive and brain-penetrant inhibitor of adaptor protein-2 associated kinase 1 (AAK1) with an IC 50 of 3.3 nM and a K i of 0.9 nM, respectively. LP-935509 is also a potent inhibitor of BIKE ( IC 50 =14 nM) and a modest inhibitor of GAK ( IC 50 =320 nM). LP-935509 shows antinociceptive activity. LP-935509 can be used for neuropathic pain and SARS-CoV-2 research In Vitro LP-935509 inhibits μ2 phosphorylation with an IC 50 value of 2.8 ± 0.4 nM, inhibits phosphorylation of a peptide derived from the μ2 protein with an IC 50 value of 3.3 ± 0.7 nM. LP-935509 exhibits a dose-dependent inhibition of the SARS-CoV-2 S-RBD internalization into host cells. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo LP-935509 (0-60 mg/kg; PO, single) causes a robust reduction in pain behavior . LP-935509 (0.1-30 mg/kg; PO, single dosage) causes a dose-dependent reversal of thermal hyperalgesia in CCI model . LP-935509 (IV (1 mg/kg) or orally (10 mg/kg); once) has 100% oral bioavailability and a plasma half life of 3.6 hours . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Male C57BL/6J mice (with SNL(spinal nerve ligation) injury, n=8-10 male mice per group) Dosage: 0, 10, 30 and 60 mg/kg (10 ml/kg) Administration: PO, single Result: Caused a dose-dependent reduction in phase II paw flinches that was significantly lower than the vehicle-treated animals; exhibited a dose-dependent reversal of the mechanical allodynia; Caused a robust reduction in pain behavior. Animal Model: Male Sprague-Dawley rats (CCI (chronic constriction injury)-operated rats) Dosage: 0, 0.1, 0.3, 1, 3, 10, or 30 mg/kg Administration: PO, two daily, for 5 days Result: Caused a dose-dependent reversal of thermal hyperalgesia, cold allodynia, mechanical allodynia, and mechanical hyperalgesia in CCI animals. Reversed the behavioral deficits, with ED 50 values ranging from 2 mg/kg to 10 mg/kg. Animal Model: Male Sprague-Dawley rats Dosage: 1 mg/kg (IV), 10 mg/kg (PO) Administration: IV, PO; once (Pharmacokinetic Analysis) Result: Had 100% oral bioavailability and a plasma half life of 3.6 hours; The Cmax for the 10 mg/kg oral dose was 5.2 µM at 0.5-hour postdose; had a plasma-free fraction of 2.6% in mice. Brain drug levels exceeded plasma drug levels with a brain/plasma drug ratio typically between 3 and 4, showing that LP-935509 was highly brain-penetrant. Form:Solid IC50& Target:IC50: 3.3 ± 0.7 nM (AAK1), 14 nM (BIKE), 320 ± 40 nM (GAK)

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