Small Molecule Kv1.3 Blockers as New Therapeutics for Multiple Sclerosis

小分子 Kv1.3 阻滞剂作为多发性硬化症的新疗法

• 批准号: 7014330
• 负责人: HEIKE WULFF
• 金额: $ 17.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014330
• 关键词: T lymphocyte; cell mediated lymphocytolysis test; chemical models; chemical structure function; clinical research; cytotoxicity; disease /disorder model; drug design /synthesis /production; drug discovery /isolation; drug receptors; drug screening /evaluation; experimental allergic encephalomyelitis; high performance liquid chromatography; human subject; ion channel blocker; laboratory rat; multiple sclerosis; mutagen testing; nanomedicine; passive immunization; pharmacokinetics; potassium channel; psoralens; small molecule; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that affects approximately 0.4 million people in the US and more than 2 million worldwide. Memory T cells specific for components of the myelin sheath appear to be crucial for the pathogenesis of MS. With the voltage-gated potassium channel Kv1.3 we have recently identified an exciting new molecular target that allows selective pharmacological suppression of effector memory T (TEM) cells. Expression of this channel is increased in both CD4+ and CD8+ TEM cells and Kv1.3 blockers have been shown to potently suppress their proliferation without impairing the function of naive and central memory T cells. We have further validated Kv1.3 as a new therapeutic target for MS by demonstrating that myelin-reactive T cells from patients with MS are predominantly Kv1.3-high TEM cells and that the Kv1.3 blocking peptide ShK can treat EAE in rats. Despite Kv1.3's obvious therapeutic importance, specific and potent small molecule inhibitors of Kv1.3 have so far not been developed by the pharmaceutical industry. Following up on anecdotal reports from the late 1980s that tea prepared from Ruta graveolens, the common rue, had beneficial effects in MS, we discovered that Ruta contained a small molecule called 5-methoxypsoralen (5-MOP), which blocks Kv1.3 in the micromolar range. Using 5-MOP as a template we started a medicinal chemistry effort and have since then improved the potency of the alkoxypsoralens into the low nanomolar range and proposed an essential pharmacophore for small molecule Kv1.3 blockers. Our most potent compound so far is PAP-1, which inhibits Kv1.3 with a Kd of 2 nM and displays 22-fold selectivity over the cardiac K+ channel Kv1.5. Under Aim-1 of this proposal we intend to further explore the structure-activity relationship (SAR) around our pharmacophore model in order to further improve the potency and selectivity of our compounds. Under Aim-2 we will then test the best new compounds in adoptive-transfer EAE, an animal model of MS. The overall goal of this proposal is to obtain an ideal small molecule Kv1.3 blocker for pre-clinical development as a new drug candidate for MS. Lay: In multiple sclerosis the immune system attacks proteins in the brain of afflicted patients. The aim of this study is to identify and test new drugs that can suppress the white blood cells that are invading the brain.

描述（由申请人提供）： 多发性硬化症 (MS) 是一种中枢神经系统慢性炎症性疾病，影响美国约 40 万人，全球影响超过 200 万人。髓鞘成分特异性的记忆 T 细胞似乎对于多发性硬化症的发病机制至关重要。通过电压门控钾通道 Kv1.3，我们最近发现了一个令人兴奋的新分子靶点，它可以选择性地药理抑制效应记忆 T (TEM) 细胞。该通道的表达在 CD4+ 和 CD8+ TEM 细胞中均增加，并且 Kv1.3 阻断剂已被证明可以有效抑制其增殖，而不损害初始 T 细胞和中枢记忆 T 细胞的功能。我们通过证明来自多发性硬化症患者的髓磷脂反应性 T 细胞主要是 Kv1.3 高 TEM 细胞，并且 Kv1.3 阻断肽 ShK 可以治疗大鼠的 EAE，进一步验证了 Kv1.3 作为多发性硬化症的新治疗靶点。尽管Kv1.3具有明显的治疗重要性，但迄今为止制药行业尚未开发出特异性且有效的Kv1.3小分子抑制剂。根据 20 世纪 80 年代末的轶事报道，用芸香（常见的芸香）制成的茶对多发性硬化症有有益作用，我们发现芸香中含有一种名为 5-甲氧基补骨脂素 (5-MOP) 的小分子，它可以阻断 Kv1.3微摩尔范围。使用 5-MOP 作为模板，我们开始了药物化学研究，此后将烷氧基补骨脂素的效力提高到低纳摩尔范围，并提出了小分子 Kv1.3 阻滞剂的基本药效团。迄今为止，我们最有效的化合物是 PAP-1，它能抑制 Kv1.3，Kd 为 2 nM，并且对心脏 K+ 通道 Kv1.5 的选择性高出 22 倍。根据该提案的目标 1，我们打算进一步探索我们的药效团模型的构效关系 (SAR)，以进一步提高我们化合物的效力和选择性。在 Aim-2 下，我们将在过继转移 EAE（一种多发性硬化症动物模型）中测试最好的新化合物。该提案的总体目标是获得一种理想的小分子 Kv1.3 阻断剂，用于临床前开发，作为 MS 的新候选药物。 Lay：在多发性硬化症中，免疫系统会攻击患者大脑中的蛋白质。这项研究的目的是识别和测试可以抑制侵入大脑的白细胞的新药物。