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

描述（由申请人提供）： 多发性硬化症（MS）是一种中枢神经系统的慢性炎症性疾病，在美国影响约40万人，在全球影响超过200万人。特定于髓鞘成分的记忆T细胞似乎对MS的发病机制至关重要。随着电压门控钾通道Kv1.3，我们最近发现了一个令人兴奋的新分子靶点，允许选择性药理学抑制效应记忆T（TEM）细胞。该通道的表达在CD 4+和CD 8 + TEM细胞中均增加，并且Kv1.3阻断剂已显示出有效抑制它们的增殖而不损害幼稚和中枢记忆T细胞的功能。我们进一步验证了Kv1.3作为MS的新治疗靶点，证明MS患者的髓鞘反应性T细胞主要是高Kv1.3的TEM细胞，并且Kv1.3阻断肽ShK可以治疗大鼠的EAE。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和有效的Kv1.3小分子抑制剂。根据20世纪80年代末的轶事报道，从Ruta graveolens（常见的芸香）制备的茶对MS有有益的影响，我们发现Ruta含有一种名为5-甲氧基补骨脂烯（5-MOP）的小分子，它在微摩尔范围内阻断Kv 1.3。使用5-MOP作为模板，我们开始了药物化学的努力，并从那时起提高了alkoxypeptiens的效力到低纳摩尔范围，并提出了一个小分子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，其抑制Kv1.3的Kd为2 nM，并显示出比心脏K+通道Kv1.5高22倍的选择性。在该提案的目标-1下，我们打算进一步探索药效团模型周围的结构-活性关系（SAR），以进一步提高我们化合物的效力和选择性。在目标-2下，我们将在过继转移EAE（MS的动物模型）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阻滞剂，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，免疫系统攻击患者大脑中的蛋白质。这项研究的目的是鉴定和测试可以抑制侵入大脑的白色血细胞的新药。

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.