Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure–Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides
- 5 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (11), 6107-6133
- https://doi.org/10.1021/acs.jmedchem.0c00361
Abstract
Voltage gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic SAR studies carried out to identify novel sulfonamide derivatives as potent, selective and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5 and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43 and 51 have shown favorable PK profile across different species and robust efficacy in veratridine and formalin induced inflammatory pain models in mice. Compound 51 has also shown significant effect in CCI induced neuropathic pain model. Profile of 51 has indicated that it has the potential for further evaluation as a therapeutic for pain.Keywords
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