AI Article Synopsis
- Recent studies on mice suggest that AAK1 could be a promising target for treating neuropathic pain, which led to the development of a new drug called BMS-986176/LX-9211 that is currently in phase II trials.
- Researchers also discovered additional highly selective and effective AAK1 inhibitors through structure-activity relationship studies, which showed promising results in neuropathic pain models with strong ability to penetrate the CNS.
- Among these compounds, one central pyridine isomer proved to be four times more potent than BMS-986176/LX-9211 with better efficacy but had a less favorable toxicity profile in preclinical tests.
Article Abstract
Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds and showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties. Compound , a central pyridine isomer of BMS-986176/LX-9211 (), was 4-fold more potent than in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to in the CCI rat model. However, both and showed an inferior preclinical toxicity profile compared to .
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| http://dx.doi.org/10.1021/acs.jmedchem.1c02132 | DOI Listing |
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