Voltage-gated sodium (Nav) channels present untapped therapeutic value for better and safer pain medications. The Nav1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. In addition, the relevance of rodent pain assays to the human condition is under increasing scrutiny as a number of mechanisms (or at the very least molecules) that are active in rodents have not translated to humans, and direct impact on pain fibers has not been confirmed in vivo. In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Nav1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Nav1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Nav1.8 inhibition broadly.

中文翻译：

---

通过选择性抑制恒河猴 Nav1.8 进行镇痛和外周 c 纤维调节。


电压门控钠 （Nav） 通道为更好、更安全的止痛药提供了尚未开发的治疗价值。Nav1.8 通道亚型特别令人感兴趣，因为它位于外周疼痛纤维上，并在啮齿动物临床前疼痛和神经生理学测定中被证明的作用。迄今为止，还没有该通道的抑制剂被批准作为治疗人类疼痛状况的药物，这可能是因为开发一种具有足够选择性的药物样分子，不仅在人类中而且在对药物发现的临床前开发路径至关重要的临床前物种中都存在挑战。此外，啮齿动物疼痛测定与人类状况的相关性正受到越来越多的审查，因为许多活跃在啮齿动物中的机制（或至少是分子）尚未转化为人类，并且对疼痛纤维的直接影响尚未在体内得到证实。在本报告中，我们利用了非人灵长类动物的众多生理终点来评估一种新型、有效和选择性的 Nav1.8 抑制剂化合物 MSD199 的镇痛和药效学活性。这些药效学生物标志物为 Nav1.8 抑制对灵长类动物外周疼痛纤维的体内影响提供了重要证实，并且具有很高的临床转化潜力。因此，这些发现可能会大大提高转化药物发现工作的成功率，以获得更好的、更安全的止痛药，以及广泛地理解 Nav1.8 抑制的灵长类动物生物学。