Development of Novel Class of Anti-Inflammatory Drugs

描述（由申请人提供）：炎症性肠病（IBD）是一种慢性，反复发作的胃肠道疾病，在美国折磨着超过140万人。目前IBD的治疗是中等成功的，结果是显著的不良副作用，包括免疫抑制和恶性肿瘤。最近，我们已经确定了LANCL2作为一个新的治疗靶点，并特别发现61610，一种双（苯并吡唑基）对苯二甲酸酯类化合物，在小鼠IBD模型中具有有效的抗炎活性。拟议的SBIR I期的具体目标是：Aim 1将验证LANCL2作为IBD的新治疗靶点。位点特异性、原子分辨率受体-配体结合研究将提供与药物治疗靶标结合相关的最详细信息，并有助于合理设计和发现新型激动剂。等温滴定量热法（ITC），一种无标记热力学技术，以及基于荧光的分析将用于量化LANCL2与其配体（即脱落酸（ABA）和61610）之间的结合亲和力和反应化学计量学。之前，我们和其他人发现ABA与LANCL2结合，激活cAMP的产生并激活蛋白激酶A （PKA）。因此，我们将探索61610对cAMP/PKA信号传导的下游影响。目的二将评估双（苯并咪唑基）对苯二甲酸类抗炎化合物治疗肠道炎症的疗效。为了优化双（苯并米达唑基）对苯二甲酸类药物抗炎症IBD的药效，我们将(1)生成20-50个61610的衍生物和类似物，(2)基于LANCL2结合、cAMP/PKA信号和排除PPAR γ激活进行化合物筛选，选择3个先导衍生物/类似物进行体内进一步开发，(3)比较3个先导化合物与母体化合物61610和强的松龙的口服给药效果。在IBD小鼠模型中，IBD患者使用的类固醇。SBIR II期将优化两种在小鼠肠道炎症模型中已证明有效的先导化合物，并沿着调控途径推进它们，包括功效、作用方式、吸收、分布、代谢和排泄（ADME）、药代动力学/药效学（PK/PD）、毒代动力学（TK）分析和毒性评估，以完成提交研究性新药（IND）申请所需的测试，为人体临床试验做准备。为了优化药物在肠道中的传递，我们将开发更多水溶性的基于61610的前药，并测试它们的有效性和安全性。长期目标：对于中度至重度IBD病例，BioTherapeutics技术的目标将是提供一种口服治疗替代现有治疗方法，成本更低，疗效更高，副作用更少。该技术将解决IBD患者的首要健康问题，并将提供估计超过8亿美元的巨大商业化潜力。

DESCRIPTION (provided by applicant): Inflammatory Bowel Disease (IBD), a chronic, recurring disease of the gastrointestinal tract, afflicts over 1.4 million people in the U.S. Curret therapies for IBD are modestly successful and result with significant adverse side effects, including immune suppression and malignancies. Recently, we have identified Lanthionine Synthetase Component C-Like 2 (LANCL2) as a novel therapeutic target and specifically have found that 61610, a compound of the class of bis(benzimidazoyl)terephthalanilides, exerts potent anti-inflammatory activity in mouse models of IBD. The specific aims for the proposed SBIR Phase I are: Aim One will validate LANCL2 as a novel therapeutic target for IBD. Site-specific, atomic-resolution receptor-ligand binding studies will provide the most detailed information related to drug-therapeutic target binding and facilitate a rational design and discovery of novel agonists. Isothermal titration calorimetry (ITC), a label-free thermodynamic technique, and a fluorescence-based assay will be used to quantify binding affinity and reaction stoichiometry between LANCL2 and its ligands (i.e., abscisic acid (ABA) and 61610). Previously, our group and others found that ABA binds to LANCL2 and activates cAMP production and activates protein kinase A (PKA). Thus, we will explore downstream effects of administering 61610 on cAMP/PKA signaling. Aim Two will evaluate the efficacy of the bis(benzimidazoyl)terephthalanilides class of anti- inflammatory compounds for treating gut inflammation. To optimize drug efficacy of bis(benzimidazoyl)terephthalanilides for anti-inflammatory effects in IBD, we will (1) generate 20-50 derivatives and analogs of 61610, (2) perform compound screening based on LANCL2 binding, cAMP/PKA signaling and exclusion of PPAR gamma activation to select 3 lead derivatives/analogs for further development in vivo, and (3) compare the oral administration efficacy of 3 lead compounds against the parent compound 61610 and prednisolone, a steroid used by IBD patients, in mouse models of IBD. SBIR Phase II will optimize two of the lead compounds with demonstrated efficacy in mouse model of gut inflammation and advance them along the regulatory pathway, including efficacy, mode of action, absorption, distribution, metabolism and excretion (ADME), phamacokinetics/pharmacodynamics (PK/PD), toxicokinetics (TK) analysis and toxicity assessment working towards the testing required to submit an investigational new drug (IND) application in preparation for human clinical trials. To optimize drug delivery in the gut we will develop more water-soluble 61610-based pro-drugs and test their efficacy and safety. Long Term Goal: For moderate to severe cases of IBD, the goal of BioTherapeutics technology will be to provide an oral therapeutic alternative to existing treatments that costs less and provides greater efficacy with reduced adverse side effects. The technology will address the overlying health problem with patients suffering with IBD and will provide a significant commercialization potential estimated to be over $800M.