Development of Selective Inhibitors of NaV1.7 as Therapeutics for Pain

描述(申请人提供)：与阿片类镇痛剂相关的副作用，如恶心、嗜睡、呼吸抑制和可能上瘾，正在推动设计和开发治疗急性、亚急性和慢性疼痛的新疗法。电压门控钠离子通道是一种完整的膜蛋白，负责沿导电细胞传递信号。已经对10个哺乳动物基因进行了测序，这些基因编码10个不同的通道亚型(Nav1.1-1.9和NAx)，每个亚型都具有独特的门控特性，以及细胞和组织的分布模式。最近的研究表明，人类钠离子通道亚型Nav1.7中的一种遗传性功能丧失突变与一种罕见的遗传性疾病有关，这种疾病被称为先天性疼痛不敏感(CIP)。患有CIP的患者对正常疼痛刺激的敏感度降低，感觉或认知功能没有明显缺陷。大量证据表明，在正常人中选择性抑制Nav1.7可以概括CIP的表型。人类NAV蛋白的高度同源性，加上针对多个离子通道靶点的高通量筛选的挑战，阻碍了为单个NAV亚型开发选择性拮抗剂的大部分努力。最近的发现表明，hNaV1.7孔区的两个氨基酸变异导致了一类自然产生的钠通道拮抗剂--鸟嘌呤毒素(GTxs)对这种异构体的效力降低。这种变异存在于所有已知的hNaV1.7剪接变异体中，但在任何其他人类NAV亚型中都没有发现。在我们的SBIR计划的第一阶段，设计并合成了GTx类似物，通过全细胞膜片钳电生理学检测，GTx类似物对hNaV1.7的选择性抑制优于其他NAV异构体。在我们计划的第二阶段，我们的目标是通过集中的、中等吞吐量的药物化学努力来提高我们先导化合物的选择性和药物性能，并在临床前的安全性和有效性研究中评估最有希望的止痛候选药物。这一计划的成功将导致一种或多种高亲和力、同工型选择性的Nav1.7抑制剂被提名为治疗疼痛的候选药物。

DESCRIPTION (provided by applicant): Side effects associated with opioid analgesics, such as nausea, drowsiness, respiratory depression, and potential for addiction, are motivating the design and development of new therapies for acute, subacute and chronic pain. Voltage-gated Na+ ion channels are integral membrane proteins responsible for the transmission of signals along electrically conducting cells. Ten mammalian genes have been sequenced, which encode ten distinct channel isoforms (NaV1.1-1.9 and NaX), each having unique gating properties, and cellular and tissue distribution patterns. Recent studies have correlated a hereditary loss-of-function mutation in one human Na+ channel isoform - NaV1.7 - with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Individuals with CIP have reduced sensitivity to normally painful stimuli without significant deficits to sensory or cognitive function. A compellin body of evidence indicates that selective inhibition of NaV1.7 in normal humans could recapitulate the phenotype of CIP. The high homology of human NaV proteins, coupled with challenges associated with high-throughput screening against multiple ion channel targets, have thwarted most efforts to develop selective antagonists for individual NaV subtypes. Recent findings indicate that a two amino acid variation in the pore region of hNaV1.7 is responsible for reduced potency of a family of naturally-occurring sodium channel antagonists, the guanidinium toxins (GTxs), against this isoform. This variation is present in all known hNaV1.7 splice variants, but is not found in any other human NaV isoform. In Phase I of our SBIR program, GTx analogues were designed and synthesized that exhibit selective inhibition of hNaV1.7 over other NaV isoforms as measured by whole-cell patch clamp electrophysiology. In Phase 2 of our program, we aim to improve the selectivity and drug properties of our lead compounds with a focused, medium-throughput medicinal chemistry effort, and to evaluate the most promising candidates as therapeutics for pain in preclinical safety and efficacy studies. Success of this program will lead to the nomination of one or more high-affinity, isoform-selective inhibitors of NaV1.7 as drug candidates for pain treatment.