Adenosine-3 agonists for the suppression of arthritis

描述(由申请人提供)：基于在体外和体内的前景 VIVO数据，申请者正在开发新类别的化合物 具有抗炎作用，并具有抗关节炎的潜力。在这份提案中， 我们提出的证据表明，腺苷-3受体的部分配体是(1) 巨噬细胞源性促炎介质产生的抑制物 和促进剂在体外和体内产生抗炎介质 体内(2)强效抗炎药在多种炎症中的作用 条件包括胶原诱导的关节炎和内毒素诱导的全身性 发炎。申请者打算开发一种精选的腺苷3受体 作为抗关节炎药物的激动剂。申请者与一个 腺苷受体配基领域的杰出群体，并已确定 候选者，对人类系统中的腺苷3亚型有选择性， 它们被认为是进一步药物开发、疗效研究的合适线索， 以及最终的正式药代动力学和毒理学研究。具体目标 本建议的目的是(1)鉴定先导腺苷-3配体，具有 人体系统中可接受的疗效曲线(2)，用于进行疗效研究 与该化合物在抑制促炎介质方面的作用 人类细胞系统(3)合成更大的GLP和GMP质量的数量 先导腺苷-3激动剂化合物，以及(4)进行内部和 转包的两个物种的药代动力学和毒性研究 FDA的要求。目前的工作范围将使申请者提前 到IND应用程序的级别，以进行选定的 腺苷-3配体。 拟议的商业应用：一种新的、有效的关节炎治疗方法在国内市场的年销售额估计为10亿美元。据估计，全球市场规模为40亿美元。目前的市场进入者并不完全有效：与关节炎相关的发病率很高，有慢性残疾、失业和运动不耐受。一种新的A3受体激动剂可能是当前治疗方案的有用的抗炎辅助药物；目前SBIR第二阶段的资金将允许在两年内开始人类安全试验。

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.