Medicinal Chemistry Based Optimization of Lead Compounds Against Multiple Scleros

描述（由申请人提供）：多发性硬化症（MS）是一种影响中枢神经系统（CNS）的自身免疫性疾病，在美国许多成年人中导致神经和临床残疾。 患者脑和脊髓中的白细胞浸润和脱髓鞘斑块是MS的标志。目前，对于这种使人衰弱的疾病没有治愈方法，也很少有治疗方法。 该疾病主要在免疫调节剂的帮助下进行管理，其具有不同程度的有效性，并且几乎所有都具有显著的副作用。 减少白细胞浸润是非常有益的，并降低了疾病的严重程度和发病机制。 然而，这种阻断疗法也显示出意想不到的副作用，包括几例患者的PML病例，这表明需要一种新的方法。 白细胞粘附受体整合素CD 11b/CD 18（Mac- 1，<$M <$2）是这些细胞的各种生物学功能的核心。 CD 11b/CD 18也是MS中一个公认的靶点。由于先前使用抗体和配体模拟物阻断CD 11b/CD 18功能的方法（抗粘附疗法）在几项临床试验中失败，我们寻求一种替代方法来减少白细胞迁移和浸润，该方法涉及增强细胞粘附而不是阻断它。 （Adhaere）开发了新型CD 11b/CD 18小分子激动剂，其结合CD 11b/CD 18并增强CD 11b/CD 18介导的细胞粘附。 虽然违反直觉，但增加细胞粘附减少白细胞迁移并减少其体内运输。 Adhaere的化合物（称为leukadherins）显示出对CD 11b/CD 18的高选择性和在多种炎症损伤实验模型中的高疗效，包括MS的EAE模型。因此，这些化合物是治疗人类患者MS的有希望的新治疗候选物。 然而，先导化合物显示出低微摩尔效力，差的水溶性，因此，需要一些化学/结构优化。 此外，先导中心支架含有噻唑烷酮基序，其可以 易于修饰以进一步提高先导化合物的效力和生物利用度。 该提案的总体目标是从化学上完善和充分发展这一先进的家族。 类铅分子。 在体内PK和疗效评价之前，将在体外ADME-T试验中对优化的化合物进行检测。 我们的长期目标是将这些先导化合物开发成FDA监管的、可用于治疗人类MS的候选药物。 本文提出的研究将导致开发用于治疗人类MS的新型治疗剂。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS) and results in neurological and clinical disability i number of adults in the US. Leukocyte infiltration and plaques of demyelination in the brain and spinal cord of patients are a hallmark of MS. Currently, there is no cure and few therapies for this debilitating disease. The disease is being primarily managed with the help of immuno- modulators with varying degree of effectiveness and almost all having significant side-effects. Reducing leukocyte infiltration is highly beneficial and decreases the severity and disease pathogenesis. However, such blocking therapies have also shown unexpected side effects, including cases of PML in several patients, suggesting that a novel approach is desirable. The leukocytic adhesion receptor integrin CD11b/CD18 (Mac- 1, ¿M¿2) is central to the various biological functions of these cells. CD11b/CD18 is also a well-established target in MS. Since the prior approaches using antibodies and ligand mimics to block the function of CD11b/CD18 (anti-adhesion therapy) failed in several clinical trials, we pursued an alternative approach for reducing leukocyte migration and infiltration that involves enhancing cell adhesion rather than blocking it. Adhaere Pharmaceuticals, Inc. (Adhaere) has developed novel CD11b/CD18 small molecule agonists that bind to CD11b/CD18 and enhance CD11b/CD18-mediated cell adhesion. While counter-intuitive, increasing cell adhesion reduces leukocyte migration and decreases their trafficking in vivo. Adhaere's compounds (termed leukadherins) show high selectivity for CD11b/CD18 and high efficacy in multiple experimental models of inflammatory injury, including the EAE model of MS. Therefore, these compounds are promising new therapeutic candidates for treating MS in human patients. However, the lead compounds show low micromolar potency, poor aqueous solubility and, thus, need some chemical/structural optimization. Additionally, the lead central scaffold contains a thiazolidine-one motif, which can easily be modified to further improve the potency and bioavailability of the lead compounds. The overall goal of this proposal is to chemically refine and fully develop this family of first-in class lead molecules. The optimized compounds will be tested in in vitro ADME-T assays prior to their in vivo PK and efficacy evaluations. Our long-term goal is to develop these leads into FDA-regulated, pharmacologically useful drug candidates for treating MS in humans. The studies proposed here will lead to the development of novel therapeutic agents for treating MS in humans.