Riluzole Prodrugs for Melanoma and ALS

治疗黑色素瘤和 ALS 的利鲁唑前药

• 批准号: 8057154
• 负责人: Allen Bernard Reitz
• 金额: $ 33.63万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-27 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057154
• 关键词: Achievement; Address; Adverse effects; Amyotrophic Lateral Sclerosis; Animals; Apoptotic; Autopsy; Back; Behavioral; Benchmarking; Biological; Biological Assay; Blood Circulation; Cell Death; Cell Respiration; Characteristics; Chemicals; Cleaved cell; Clinic; Clinical; Clinical Trials; Cytochrome P-450 CYP1A2; Cytotoxic agent; Dacarbazine; Development; Drug Exposure; Drug Kinetics; Ensure; Evaluation; FDA approved; Family; Future; Goals; Hair; Half-Life; Headache; Hepatic; Hour; Human; Immunodeficient Mouse; In Vitro; Individual; Intellectual Property; Intestines; Investigational New Drug Application; Liquid substance; Liver; Liver Microsomes; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Metabolic; Metabolic Clearance Rate; Metabolism; Metastatic Melanoma; Methods; Mus; N hydroxylation; Oral Administration; Organ; Organic Synthesis; Parents; Patients; Pharmaceutical Preparations; Phase; Plasma; Preparation; Primary Lateral Sclerosis; Problem Solving; Process; Prodrugs; Program Development; Property; Rattus; Relative (related person); Riluzole; Rodent; Series; Serum; Simulate; Staging; Stomach; Survival Rate; Techniques; Testing; Therapeutic; Time; Toxicology; Transgenic Mice; Validation; Vomiting; Xenograft procedure; aqueous; arm; base; cancer type; chemical stability; chemotherapy; clinical efficacy; commercialization; compliance behavior; design; drug candidate; drug distribution; drug metabolism; hemodynamics; human subject; improved; in vitro activity; in vivo; in vivo Model; melanoma; mouse model; novel; outcome forecast; pre-clinical; programs; response; standard of care; success; treatment duration; tumor

DESCRIPTION (provided by applicant): Metastatic melanoma has few treatment options, and the current therapeutic standard of care is dacarbazine which is a highly cytotoxic drug with severe side effects including vomiting, headache and hair loss. Treatment with dacarbazine has a median progression-free enhancement of survival time of only 1.5 months. Riluzole (RilutekTM) is a non-toxic drug and the only FDA-approved treatment for amytrophic lateral sclerosis (ALS or Lou Gehrig's disease). We have recently shown that riluzole has dramatic anti-melanoma activity in vitro, in mice and in a Phase 0 human clinical trial. In the clinic, four of twelve melanoma patients showed significant clinical or radiologic evidence of Stage III and IV tumor response. These results, along with the mild side-effect profile that riluzole has shown among ALS patients, suggests that this drug has significant potential for use as an improved treatment for metastatic melanoma. However, the therapeutic utility of riluzole itself in ALS and eventually for melanoma is very constrained by rapid first-pass metabolism in the liver and an exceptionally high level of patient-to-patient variability in the extent of the Cyp1A2-mediated oxidative metabolism that is observed. We propose to solve this problem using a strategy in which prodrugs of riluzole having enhanced stability to hepatic metabolism are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. Four different series of riluzole prodrugs will be prepared and evaluated for their chemical and enzymatic stability at differing pHs, in simulated gastric and intestinal fluid, in serum, and in rat and human liver microsomes. Prodrugs having a range of stability and cleavage profiles, but generally with projected t1/2 values of 1-4 hrs, will be evaluated for anti- melanoma activity using the same in vitro and murine melanoma assays which we have previously used to evaluate riluzole. Comparison of riluzole-, prodrug- and vehicle-treated animals will establish the advantage in efficacy (ED50) of individual prodrugs against melanoma. Full pharmacokinetic analysis will establish improvements in drug exposure, clearance and biological half-life. Our goal is to reposition riluzole-based therapy for the treatment of metastatic melanoma by the successful application of a prodrug strategy to solve the current drug metabolism and distribution limitations of riluzole itself. PUBLIC HEALTH RELEVANCE: Metastatic melanoma is a type of cancer having extremely low survival rates and very limited treatment options based on highly toxic chemotherapy agents. Riluzole is a non- toxic drug approved for amyotrophic lateral sclerosis (ALS). We have recently shown exciting preliminary results for riluzole treatment of metastatic melanoma in mice and human subjects. But because of differences in how individuals metabolize riluzole, it will be difficult for this drug to realize its full potential as a treatment for metastatic melanoma. In this application, we propose to design, synthesize and evaluate novel drug candidates which will release riluzole in a more predictable and longer-acting way, leading to improved therapies for metastatic melanoma.

描述（由申请人提供）：转移性黑色素瘤的治疗选择很少，目前的治疗标准是达卡巴嗪，这是一种具有严重副作用（包括呕吐、头痛和脱发）的高细胞毒性药物。达卡巴嗪治疗的中位无进展生存期延长仅为1.5个月。阿舒唑（阿舒唑TM）是一种无毒药物，也是FDA批准的唯一治疗肌萎缩性侧索硬化症（ALS或Lou Gehrig病）的药物。我们最近在体外、小鼠和0期人体临床试验中发现利鲁唑具有显著的抗黑色素瘤活性。在临床中，12例黑色素瘤患者中有4例显示出III期和IV期肿瘤缓解的显著临床或放射学证据。这些结果，沿着利鲁唑在ALS患者中表现出的轻微副作用，表明这种药物具有显著的潜力，可用于改善转移性黑色素瘤的治疗。然而，利鲁唑本身在ALS和最终用于黑色素瘤中的治疗效用受到肝脏中快速首过代谢和观察到的Cyp 1A 2介导的氧化代谢程度的异常高水平的患者间变异性的限制。我们提出使用一种策略来解决这个问题，其中通过口服给药将对肝代谢具有增强的稳定性的利鲁唑前药递送到体循环中，然后通过酶促或一般生物物理释放过程裂解以在血浆中释放利鲁唑。将制备四种不同系列的利鲁唑前药，并评价其在不同pH值下、在模拟胃液和肠液中、在血清中以及在大鼠和人肝微粒体中的化学和酶稳定性。将使用我们先前用于评价利鲁唑的相同体外和鼠黑素瘤测定来评价具有一定范围的稳定性和切割特征但通常具有1-4小时的预计t1/2值的前药的抗黑素瘤活性。比较利鲁唑、前药和媒介物处理的动物将确定单个前药针对黑素瘤的功效（ED 50）的优势。完整的药代动力学分析将确定药物暴露、清除率和生物半衰期的改善。我们的目标是重新定位利鲁唑为基础的治疗转移性黑色素瘤的前药策略的成功应用，以解决目前的药物代谢和分布的限制利鲁唑本身。 公共卫生关系：转移性黑色素瘤是一种具有极低存活率和基于高毒性化疗剂的非常有限的治疗选择的癌症。阿曲唑是一种被批准用于肌萎缩侧索硬化症（ALS）的无毒药物。我们最近已经显示了令人兴奋的初步结果利鲁唑治疗转移性黑色素瘤的小鼠和人类受试者。但由于个体代谢利鲁唑的方式存在差异，这种药物很难充分发挥其治疗转移性黑色素瘤的潜力。在本申请中，我们提出设计、合成和评估新型候选药物，这些候选药物将以更可预测和更长效的方式释放利鲁唑，从而改善转移性黑色素瘤的治疗。

项目成果

Intramolecular Rearrangement of α-Amino Acid Amide Derivatives of 2-Aminobenzothiazoles.

2-氨基苯并噻唑的α-氨基酸酰胺衍生物的分子内重排。

• DOI: 10.1016/j.tetlet.2014.05.046
• 发表时间: 2014
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Pelletier,JeffreyC;Velvadapu,Venkata;McDonnell,MarkE;Wrobel,JayE;Reitz,AllenB
• 通讯作者: Reitz,AllenB