Description
LP-935509 is a potent inhibitor of the Adapter protein-2 Associated Kinase 1 (AAK1).
Uses
LP-935509 is an orally active, potent, selective, ATP-competitive and brain-penetrant inhibitor of adaptor protein-2 associated kinase 1 (AAK1) with an IC50 of 3.3 nM and a Ki of 0.9 nM, respectively. LP-935509 is also a potent inhibitor of BIKE (IC50=14 nM) and a modest inhibitor of GAK (IC50=320 nM). LP-935509 shows antinociceptive activity. LP-935509 can be used for neuropathic pain and SARS-CoV-2 research[1].
in vivo
LP-935509 (0-60 mg/kg; PO, single) causes a robust reduction in pain behavior[1].
LP-935509 (0.1-30 mg/kg; PO, single dosage) causes a dose-dependent reversal of thermal hyperalgesia in CCI model[1].
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[1].
| Animal Model: | Male C57BL/6J mice (with SNL(spinal nerve ligation) injury, n=8-10 male mice per group)[1] |
| 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)[1] |
| 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 ED50 values ranging from 2 mg/kg to 10 mg/kg. |
| Animal Model: | Male Sprague-Dawley rats[1] |
| 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. |
References
[1] Kostich W, et al. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain. J Pharmacol Exp Ther. 2016 Sep;358(3):371-86. DOI:
10.1124/jpet.116.235333[2] Mushtaq, et al. Role Of Endocytic Machinery Regulators in EGFR Traffic and Viral Entry (2021). Theses & Dissertations. 532.
[3] QINFANG LIU. Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration[J]. Science Signaling, 2021, 14 693. DOI:
10.1126/scisignal.abg3555
