Discovery of a selective, state-independent inhibitor of NaV1.7 by modification of guanidinium toxins
Hassan Pajouhesh, Jacob T. Beckley, Anton Delwig, Holly S. Hajare, George Luu, Dennis Monteleone, Xiang Zhou, Joseph Ligutti, Shanti M. Amagasu, Bryan D. Moyer, David C. Yeomans, J. Du Bois, John V. Mulcahy
Abstract
Abstract The voltage-gated sodium channel isoform Na V 1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function Na V 1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate Na V 1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting Na V 1.7 have been advanced to clinical development, no Na V 1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a Na V 1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC 50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, Na V 1.1–1.6 and Na V 1.8. In contrast to other Na V 1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting Na V 1.7.