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

描述（由申请人提供）：与阿片类镇痛药相关的副作用，如恶心、嗜睡、呼吸抑制和成瘾的可能性，正在推动急性、亚急性和慢性疼痛新疗法的设计和开发。电压门控Na+离子通道是负责沿沿着导电细胞传递信号的完整膜蛋白。已经对10个哺乳动物基因进行了测序，它们编码10种不同的通道亚型（NaV1.1-1.9和NaX），每种亚型都具有独特的门控特性以及细胞和组织分布模式。最近的研究表明，一种人类Na+通道亚型- NaV1.7 -中的遗传性功能丧失突变与一种称为先天性疼痛不敏感（CIP）的罕见遗传性疾病相关。CIP患者对正常疼痛刺激的敏感性降低，但感觉或认知功能无明显缺陷。大量令人信服的证据表明，选择性抑制正常人的NaV1.7可以重现CIP的表型。人类NaV蛋白的高度同源性，加上与针对多个离子通道靶标的高通量筛选相关的挑战，阻碍了开发针对单个NaV亚型的选择性拮抗剂的大多数努力。最近的研究结果表明，hNaV1.7的孔区域中的两个氨基酸的变化是负责天然存在的钠通道拮抗剂，胍毒素（GTX），对这种亚型的家庭的效力降低。这种变异存在于所有已知的hNaV1.7剪接变体中，但在任何其他人类NaV同种型中均未发现。在我们SBIR项目的I期中，设计并合成了GTx类似物，其通过全细胞膜片钳电生理学测量显示出对hNaV1.7的选择性抑制超过其他NaV亚型。在我们项目的第二阶段，我们的目标是通过集中的中等通量药物化学工作来提高我们的先导化合物的选择性和药物特性，并在临床前安全性和有效性研究中评估最有前途的候选药物作为疼痛治疗药物。该计划的成功将导致一种或多种高亲和力，亚型选择性抑制剂的NaV1.7作为疼痛治疗的候选药物的提名。

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.