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。多发性硬化症患者的大脑和脊髓中的白细胞浸润和脱髓鞘斑块是多发性硬化症的一个标志。目前，这种使人衰弱的疾病没有治愈方法，治疗方法也很少。这种疾病主要是在免疫调节剂的帮助下治疗的，这些调节剂的效果不同，而且几乎都有明显的副作用。减少白细胞浸润是非常有益的，可以降低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，包括一些患者的PML病例，这表明一种新的方法是可取的。白细胞粘附受体整合素CD11b/CD18 （Mac- 1，¿M¿2）对这些细胞的各种生物学功能至关重要。由于先前使用抗体和配体模拟物阻断CD11b/CD18功能（抗黏附治疗）的方法在几次临床试验中失败，我们寻求一种减少白细胞迁移和浸润的替代方法，包括增强细胞黏附而不是阻断它。Adhaere Pharmaceuticals, Inc. （Adhaere）开发了新型CD11b/CD18小分子激动剂，可结合CD11b/CD18并增强CD11b/CD18介导的细胞粘附。虽然与直觉相反，增加细胞粘附会减少白细胞迁移并减少它们在体内的贩运。Adhaere的化合物（称为白细胞粘附素）对CD11b/CD18具有高选择性，在多种炎症损伤实验模型（包括多发性硬化症EAE模型）中具有很高的疗效。因此，这些化合物有望成为治疗人类多发性硬化症的新候选药物。然而，先导化合物的微摩尔效价低，水溶性差，因此需要进行一些化学/结构优化。此外，铅中心支架含有一个噻唑烷- 1基序，它可以

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.