Novel A2A Adenosine Agonists in Vascular Protection

描述(由申请人提供)：这是一项第二阶段的SBIR提案，旨在开发一种新的药物洗脱支架以防止再狭窄。这是腺苷治疗有限责任公司、赛特根公司和弗吉尼亚大学之间的三方合作。这里描述的工作将在腺苷治疗公司(化合物合成和药代动力学)和弗吉尼亚大学(猪支架研究)进行。纳米孔支架涂层将经过改进，以实现两种药物的最佳输送，由Setagon公司提供。这项建议的目标是证明，将两种协同抗炎化合物，即A2A腺苷受体激动剂ATL146e和加载到专利纳米孔支架涂层中的IV型磷酸二酯酶(PDE)抑制剂Rolipram结合使用，可以比目前最先进的聚合物支架涂层更有效地抑制猪的支架再狭窄。如果这些实验成功，我们的计划是开发ATL146e/Rolipram支架作为新产品。ATL146e和罗利普兰都被批准用于人类，腺苷治疗公司已经为联合使用这些化合物以防止再狭窄颁发了专利。目的1研究ATL146e和罗利普兰从支架进入血液的体外洗脱动力学。为此，我们还将利用静脉给药后从猪血中提取的化合物的液-质联用技术来确定ATL146e和罗利普兰在猪体内的最终处置半衰期。基于这些数据，我们将在支架内植入足以达到仅1 ng/kg的游离血液浓度的化合物，这些化合物不太可能产生副作用。目的2研究ATL146e+/-罗利普兰支架对猪再狭窄的影响。结果将与商业上可获得的含有西罗莫司作为黄金标准的支架进行比较。由于ATL146e和罗利普兰都已被批准用于人类，我们预计，如果这项研究的结果表明ATL146e+/-罗利普兰比西罗莫司更有效，那么将有可能启动第二阶段临床试验，在人类身上测试ATL146e/罗利普兰支架。

DESCRIPTION (provided by applicant): This is a phase II SBIR proposal to develop a new drug eluting stent to prevent restenosis. It is a 3-way collaboration between Adenosine Therapeutics, LLC, Setagon, Inc., and the University of Virginia. The work described here will be done at Adenosine Therapeutics (compound synthesis and pharmacokinetics) and the University of Virginia (Stent studies in pigs). The nanoporous stent coating will be refined for optimal delivery of two drugs and provided by Setagon, Inc. The goal of this proposal is to demonstrate that the combined used of two synergistic anti-inflammatory compounds, ATL146e, an agonist of A2A adenosine receptors, and rolipram, a type IV phosphodiesterase (PDE) inhibitor, loaded into a proprietary nanoporous stent coating, inhibits stent restenosis in pigs more effectively than current state-of-the-art polymeric stent coatings. If these experiments are successful our plan is to develop the ATL146e/rolipram stent as a new product. ATL146e and rolipram are both approved for use in man and Adenosine Therapeutics has issued patents for the combined use of these compounds to prevent restenosis. Aim 1 proposes to investigate the elution kinetics of ATL146e and rolipram from stents into blood in vitro. In this aim we also will determine the terminal disposition half-life of ATL146e and rolipram in pigs using liquid chromatography/ mass spectroscopy of compounds extracted from pig blood after intravenous administration. Based on these data we will load stents with compounds sufficient to achieve free blood concentrations of only 1 ng/kg, that are unlikely to produce side effects. Aim 2 proposes to examine restenosis in pigs of stents loaded with ATL146e+/- rolipram. The results will be compared to commercially available stents containing sirolimus as a gold standard. Since ATL146e and rolipram have both been approved for human use, we anticipate that if the results of this study show that ATL146e +/- rolipram is more effective that sirolimus, it will be possible to initiate phase II clinical trials to test ATL146e/rolipram stents in man.