5 years ago

Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors

Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors
The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.

Publisher URL: www.sciencedirect.com/science

DOI: S0960894X17306583

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