Development of Novel Class of Anti-Inflammatory Drugs

描述(申请人提供)：炎症性肠病(IBD)是一种慢性、复发性的胃肠道疾病，在美国有超过140万人患有此病。目前治疗IBD的方法不算太成功，而且有显著的副作用，包括免疫抑制和恶性肿瘤。最近，我们已经确定了羊毛硫氨酸合成酶成分C-样2(LANCL2)作为一个新的治疗靶点，并特别发现61610，一种双(苯并咪唑基)对苯二甲酰亚胺类化合物，在小鼠IBD模型中具有很强的抗炎活性。拟议的SBIR第一阶段的具体目标是：目标一将验证LANCL2作为IBD的新治疗靶点。定点、原子分辨的受体-配体结合研究将提供与药物治疗靶点结合相关的最详细的信息，并有助于合理设计和发现新的激动剂。等温滴定热法(ITC)是一种无标记热力学技术，基于荧光的分析将用于量化LANCl2与其配体(即脱落酸和61610)之间的结合亲和力和反应化学计量比。此前，我们的团队和其他人发现，ABA与LANCL2结合，激活cAMP的产生，并激活蛋白激酶A(PKA)。因此，我们将探讨61610对cAMP/PKA信号转导的下游影响。目的二评价双(苯并咪唑基)对苯二甲酰亚胺类抗炎化合物治疗肠炎的疗效。为了优化双(苯并咪唑基)对苯二甲酰亚胺的抗炎药效，我们将(1)合成20-50个衍生物和61610的类似物，(2)基于LANCL2结合、cAMP/PKA信号转导和排除PPAR Gamma激活进行化合物筛选，以选择3种领先衍生物/类似物进行体内进一步开发；(3)比较3种先导化合物在IBD小鼠模型中与母体化合物61610和强的松龙(IBD患者使用的一种类固醇)的口服疗效。SBIR第二阶段将优化两种在小鼠肠道炎症模型中被证明有效的先导化合物，并沿着调节途径推进它们，包括有效性、作用模式、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，致力于为准备人类临床试验提交研究性新药(IND)申请所需的测试。为了优化肠道给药，我们将开发更多的水溶性61610基前体药，并测试其有效性和安全性。长期目标：对于中到重度的IBD患者，生物治疗技术的目标将是提供一种替代现有治疗方法的口服治疗方法，成本更低，疗效更好，副作用更少。这项技术将解决IBD患者的潜在健康问题，并将提供巨大的商业潜力，估计超过8亿美元。

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.