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，这是一种高细胞毒性药物，具有严重的副作用，包括呕吐、头痛和脱发。达卡巴嗪治疗的中位无进展生存时间仅延长 1.5 个月。 Riluzole (RirudekTM) 是一种无毒药物，也是 FDA 批准的唯一治疗肌萎缩侧索硬化症（ALS 或 Lou Gehrig 病）的药物。我们最近在小鼠体外和 0 期人体临床试验中表明，利鲁唑具有显着的抗黑色素瘤活性。在临床上，12 名黑色素瘤患者中有 4 名显示出 III 期和 IV 期肿瘤反应的显着临床或放射学证据。这些结果，加上利鲁唑在 ALS 患者中表现出的轻微副作用，表明该药物具有改善转移性黑色素瘤治疗的巨大潜力。然而，利鲁唑本身在 ALS 以及最终黑色素瘤中的治疗效用受到肝脏快速首过代谢以及 Cyp1A2 介导的氧化代谢程度极高的患者间变异性的很大限制。观察到。我们建议使用一种策略来解决这个问题，其中对肝代谢具有增强的稳定性的利鲁唑前药通过口服递送到体循环中，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，并评估其在不同 pH 值、模拟胃液和肠液、血清以及大鼠和人肝微粒体中的化学和酶稳定性。具有一系列稳定性和裂解特性但通常具有1-4小时的预计t1/2值的前药将使用我们之前用于评估利鲁唑的相同的体外和鼠黑色素瘤测定法来评估其抗黑色素瘤活性。比较利鲁唑、前药和媒介物治疗的动物将确定各个前药对抗黑色素瘤的功效（ED50）优势。全面的药代动力学分析将确定药物暴露、清除和生物半衰期的改善。我们的目标是通过成功应用前药策略来重新定位以利鲁唑为基础的治疗转移性黑色素瘤的疗法，以解决利鲁唑本身目前的药物代谢和分布限制。 公共卫生相关性：转移性黑色素瘤是一种存活率极低且基于高毒性化疗药物的治疗选择非常有限的癌症。利鲁唑是一种被批准用于治疗肌萎缩侧索硬化症 (ALS) 的无毒药物。我们最近显示了利鲁唑治疗小鼠和人类受试者转移性黑色素瘤的令人兴奋的初步结果。但由于个体代谢利鲁唑的方式存在差异，该药物很难充分发挥其治疗转移性黑色素瘤的潜力。在此应用中，我们建议设计、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方法。

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。

• 发表时间: 2014-07-23
• 影响因子: 1.8
• 作者: Pelletier, Jeffrey C;Velvadapu, Venkata;McDonnell, Mark E;Wrobel, Jay E;Reitz, Allen B
• 通讯作者: Reitz, Allen B

Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling.

用于治疗黑色素瘤和 ALS 的利鲁唑前药：设计、合成和体外代谢分析。

• 发表时间: 2012-09-15
• 影响因子: 3.5
• 作者: McDonnell, Mark E;Vera, Matthew D;Blass, Benjamin E;Pelletier, Jeffrey C;King, Richard C;Fernandez;Smith, Garry R;Wrobel, Jay;Chen, Suzie;Wall, Brian A;Reitz, Allen B
• 通讯作者: Reitz, Allen B