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)是一种慢性中枢神经系统炎症性疾病，在美国约有40万人受到影响，全球有200多万人受到影响。针对髓鞘成分的记忆T细胞似乎在MS的发病机制中起着关键作用。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，它允许选择性地药物抑制效应记忆T(TEM)细胞。这一通道在CD4+和CD8+的TEM细胞中的表达均增加，Kv1.3阻滞剂已被证明有效地抑制了它们的增殖，而不损害初始和中央记忆T细胞的功能。我们进一步证实了Kv1.3是治疗多发性硬化的新靶点，证明了来自MS患者的髓鞘反应性T细胞主要是Kv1.3高的TEM细胞，并且Kv1.3阻断肽ShK可以治疗大鼠的EAE。尽管Kv1.3的S具有明显的治疗作用，但到目前为止，制药行业尚未开发出特异而有效的Kv1.3小分子抑制剂。根据20世纪80年代末的轶事报道，从常见的RUE中提取的茶叶对MS有好处，我们发现RUTA含有一种名为5-甲氧补骨脂素(5-MOP)的小分子，它能在微摩尔范围内阻止Kv1.3。使用5-MOP作为模板，我们开始了药物化学努力，并从那时起将烷氧类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。到目前为止，我们最有效的化合物是PAP-1，它抑制Kv1.3的Kd值为2 nM，并显示出比心脏K+通道Kv1.5高22倍的选择性。根据这项建议的目标-1，我们打算进一步探索围绕我们的药效团模型的结构-活性关系(SAR)，以进一步提高我们的化合物的效力和选择性。在Aim-2下，我们将在多发性硬化症的动物模型EAE中测试最好的新化合物。这项提议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Lay女士的新药候选：在多发性硬化症中，免疫系统攻击患者大脑中的蛋白质。这项研究的目的是识别和测试可以抑制入侵大脑的白细胞的新药。

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.