Feasibility Study of Three NCEs for Rheumatoid Arthritis

描述（由申请人提供）： 风湿性关节炎是一种潜在的致残性自身免疫性疾病，影响了200多万美国人。一般来说，关节炎药物可分为两类：NSAID（非甾体抗炎药）和DMARD（疾病修饰抗风湿药）。来氟米特是一种DMARD，由Aventis Pharmaceuticals以Aravas销售。不幸的是，它与许多副作用有关，如肝酶升高;肝损伤被归咎于一些致命的病例。 为了发现和开发一种更好的治疗风湿性关节炎的药物，我们已经制备了一系列基于来氟米特和我们的专利化合物（化合物A）的化合物，并对角叉菜胶诱导的炎症进行了体内抑制研究。基于抗炎结果，我们选择了三个最有前途的化合物（UTL-5 b，UTL-5d和UTL-5g）作为治疗风湿性关节炎的潜在候选药物。我们还进行了初步的LD 50研究，并获得了非常有希望的结果，这三个化合物。我们建议进行这项I期研究，以进一步了解和验证这三种化合物的体外抗炎和免疫抑制作用。 在第一阶段研究结束时，我们将能够在三种化合物中选择最合适的候选药物，并为第二阶段应用做准备。 本I期研究的具体目的是： (a)合成三种选定的候选药物中的每种约500 mg。 (b)开发并验证每种化合物的稳定性指示HPLC方法。 (c)研究化合物对体外原代培养的巨噬细胞的抗炎作用。 (d)研究三种候选药物的体外免疫抑制作用。 拟议的I期和II期只是开发类风湿关节炎新药的漫长旅程的开始。然而，如果I期和II期成功，该项目将基本准备好向美国食品药品监督管理局（FDA）提交IND申请，大型制药公司更有可能共同开发该项目。最终，成功的候选药物将为患有风湿性关节炎的患者提供显着改善的治疗。

DESCRIPTION (provided by applicant): Rheumatoid arthritis is a potentially crippling autoimmune disease that affects more than two million Americans. Generally arthritis drugs may be divided into two categories: NSAID (Non-steroidal Anti-Inflammatory Drug) and DMARD (Disease Modifying Anti-Rheumatic Drug). Leflunomide is a DMARD sold as Aravas by Aventis Pharmaceuticals. Unfortunately, it is associated with many side effects, such as elevated liver enzymes; liver damage was blamed for some fatal cases. In order to discover and develop a better drug for Rheumatoid Arthritis, we have made a series of compounds based on Leflunomide and our proprietary compound (compound A) and performed in vivo inhibition studies for inflammation induced by carrageenan. Based on the anti-inflammation results, we have selected three most promising compounds (UTL-5b, UTL-5d, and UTL-5g) as potential drug candidates for treating Rheumatoid Arthritis. We also performed a preliminary LD50 study and obtained very promising results for these three compounds. We are proposing to perform this Phase I study to further understand and validate the anti-inflammatory and immunosuppressant effect in vitro for these three compounds. At the end of this Phase I study, we will be able to select the most appropriate drug candidates among the three compounds and prepare for the Phase II application. The specific aims of this Phase I study are: (a) Synthesis of about 500 mg each of three selected drug candidates. (b) Develop and validate a stability-indicating HPLC method for each compound. (c) Study the anti-inflammatory effects of the compounds on primary cultures of macrophages in vitro. (d) Study the in vitro immunosuppressant effect of the three drug candidates. The proposed Phase I and Phase II are only the beginning of a long journey to developing a new drug for rheumatoid arthritis. However, if the Phase I and Phase II are successful, the project will be essentially ready for an IND filing to the Food and Drug Administration (FDA), and large pharmaceutical companies are more likely to co-develop this project. Ultimately, the successful drug candidate will provide a significantly improved therapy for patients suffering from Rheumatoid Arthritis.