Medicinal Chemistry Based Optimization of Lead Compounds Against Multiple Scleros

基于药物化学的抗多发性硬化症先导化合物的优化

• 批准号: 8455790
• 负责人: Antonio J Barbosa
• 金额: $ 30万
• 依托单位: ADHAERE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455790
• 关键词: Ablation; Adhesions; Adult; Adverse effects; Affect; Affinity; Agonist; Animal Model; Animals; Antibodies; Autoimmune Diseases; Binding; Biological Assay; Biological Availability; Biological Process; Biological Products; Blocking Antibodies; Blood Circulation; Brain; Cell Adhesion; Cell physiology; Cells; Chemicals; Clinical; Clinical Research; Clinical Trials; Data; Demyelinations; Development; Disease; Effectiveness; Endothelium; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Models; Extravasation; Family; Future; Genetic; Goals; Human; ITGAM gene; ITGB2 gene; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Integrins; Laboratories; Lead; Leukocytes; Licensing; Ligands; Macrophage-1 Antigen; Mediating; Microglia; Modeling; Modification; Molecular Conformation; Multiple Sclerosis; Neuraxis; Neurologic; Organ; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Play; Property; Publishing; Relapse; Series; Severity of illness; Solubility; Spinal Cord; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Agents; Tissues; Tysabri; adhesion receptor; analog; aqueous; base; brain tissue; cell motility; design; disability; drug candidate; drug development; efficacy evaluation; improved; in vitro Assay; in vivo; innovation; macrophage; migration; monocyte; mouse model; neutrophil; novel; novel strategies; novel therapeutics; public health relevance; receptor; research study; scaffold; small molecule; success; trafficking

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.

描述(申请人提供)：多发性硬化症(MS)是一种影响中枢神经系统(CNS)并导致神经和临床残疾的自身免疫性疾病I美国成年人数量。脑部和脊髓内的白细胞浸润和脱髓鞘斑块是MS的特征，目前对这种衰弱的疾病尚无治疗方法，治疗方法也很少。这种疾病主要是在免疫调节剂的帮助下进行治疗的，这些药物的效果各不相同，而且几乎所有药物都有明显的副作用。减少白细胞的渗透是非常有益的，并降低严重程度和疾病的发病机制。然而，这种封闭疗法也显示出意想不到的副作用，包括几名患者出现PML病例，这表明一种新的方法是可取的。白细胞黏附受体整合素CD11b/CD18(Mac-1，M？2)对这些细胞的各种生物学功能起着中心作用。CD11b/CD18也是多发性硬化症公认的靶点，由于先前使用抗体和配体模拟来阻断CD11b/CD18(抗黏附治疗)功能的方法在几个临床试验中都失败了，我们寻求另一种方法来减少白细胞的迁移和渗透，包括增强细胞黏附而不是阻断它。Adhaere制药公司(Adhaere)已开发出新型CD11b/CD18小分子激动剂，可与CD11b/CD18结合并增强CD11b/CD18介导的细胞黏附。虽然与直觉相反，但增加细胞黏附性会减少白细胞的迁移，并减少它们在体内的运输。Adaere类化合物对CD11b/CD18具有很高的选择性，在包括MS的EAE模型在内的多种炎性损伤模型中表现出较高的疗效，因此，这些化合物有望成为治疗人类MS的新的候选药物。然而，先导化合物的微摩尔效价较低，在水中的溶解性较差，因此需要一些化学/结构优化。此外，铅中心支架含有噻唑烷酮基序，它可以 易于修饰，以进一步提高先导化合物的效力和生物利用度。这项提议的总体目标是在化学上提炼和充分发展这一先进家庭 类铅分子。优化的化合物将在体外ADME-T试验中进行测试，然后再进行体内PK和疗效评估。我们的长期目标是将这些化合物开发成FDA监管的、药理上有用的候选药物，用于治疗人类多发性硬化症。这里提出的研究将导致开发用于治疗人类多发性硬化症的新型治疗剂。