Adenosine-3 agonists for the suppression of arthritis

描述（由申请人提供）：基于体外和体内有希望的结果 根据体内数据，申请人正在开发新型化合物， 抗炎作用和抗关节炎潜力。在这一提议中， 我们提出的证据表明，腺苷-3受体的选择配体是（1） 巨噬细胞衍生的促炎介质产生的抑制剂 以及体外和体内抗炎介质产生的增强剂 体内（2）在各种炎症中的强效抗炎剂 包括胶原诱导的关节炎和内毒素诱导的全身性关节炎的病症 炎症申请人打算开发一种选择的腺苷3受体， 激动剂作为抗关节炎药物。申请人与一个 在腺苷受体配体领域的突出组，并已确定 候选人，对人体系统中的腺苷3亚型具有选择性， 其被认为是进一步药物开发，功效研究， 以及最终正式的药代动力学和毒理学研究。具体目标 （1）鉴定腺苷-3前导配体， 人体系统中可接受的疗效特征（2），以进行疗效研究 在抑制促炎介质方面， 人类细胞系统（3）合成更大的，GLP和GMP质量的数量， 腺苷-3激动剂先导化合物，和（4）进行内部和 根据以下标准，分包了两个种属的药代动力学和毒性研究 FDA要求。目前的工作范围将使申请人提出 达到IND申请的水平，用于选定的I期临床试验 腺苷-3配体。 拟议的商业应用：国内市场的一种新的，有效的治疗关节炎的估计是超过10亿美元每年。 全球市场估计为40亿美元。 目前的市场进入者并不完全有效：关节炎相关的发病率很高，伴有慢性残疾、失业和运动不耐受。 一种新的A3受体激动剂可能是目前治疗方案的一种有用的抗炎辅助剂;目前SBIR II期的资金将允许在2年内开始人体安全性试验。

DESCRIPTION (provided by the applicant): Based on promising in vitro and in vivo data, the applicants are developing novel classes of compounds with anti-inflammatory effects, and with anti-arthritic potential. In this proposal, we present evidence that selected ligands of the adenosine-3 receptor are (1) inhibitors of the production of macrophage-derived pro-inflammatory mediators and enhancers of the production of anti-inflammatory mediators in vitro and in vivo (2) potent anti-inflammatory agents in a variety of inflammatory conditions including collagen-induced arthritis, and endotoxin-induced systemic inflammation. The applicants intend to develop a selected adenosine 3 receptor agonist as an anti-arthritic drug. The applicants have collaborated with a prominent group in the field of adenosine receptor ligands, and have identified candidates, with selectivity towards the adenosine 3 subtype in human systems, which are deemed suitable leads for further drug development, efficacy studies, and eventual formal pharmacokinetic and toxicology studies. The specific aims of the present proposal are (1) to identify a lead adenosine-3 ligand, with acceptable efficacy profile in human systems (2) to perform efficacy studies with the compound in terms of suppression of pro-inflammatory mediators in human cell systems (3) to synthesize larger, GLP and GMP-quality quantities of a lead adenosine-3 agonist compound, and (4) to perform in-house and subcontracted pharmacokinetic and toxicity studies in two species according to FDA requirements. The current scope of work will bring the applicants forward to the level of an IND application for Phase I clinical testing of a selected adenosine-3 ligand. PROPOSED COMMERCIAL APPLICATION: The domestic market for a novel, effective therapy for arthritis is estimated at >$1 billion per annum. Global markets are estimated at $4 billion. Current market entrants are incompletely effective: Arthritis-related morbidity is substantial, with chronic disability, loss of employment, and exercise intolerance. A novel A3 receptor agonist may represent a useful anti-inflammatory adjunct to current therapeutic regimens; funding of the current SBIR Phase II will allow for starting human safety trials in 2 years.