Novel A2A Adenosine Agonists in Vascular Protection

描述（由申请人提供）：这是一项旨在开发新型药物洗脱支架以预防再狭窄的II期SBIR提案。这是腺苷治疗有限责任公司，Setagon公司，和弗吉尼亚大学。本文描述的工作将在腺苷治疗（化合物合成和药代动力学）和弗吉尼亚大学（猪支架研究）完成。纳米多孔支架涂层将被细化，以实现两种药物的最佳递送，并由Setagon公司提供。本提案的目的是证明，将两种协同抗炎化合物ATL 146 e（A2 A腺苷受体激动剂）和咯利普兰（IV型磷酸二酯酶（PDE）抑制剂）装载到专有纳米多孔支架涂层中联合使用，比当前最先进的聚合物支架涂层更有效地抑制猪支架再狭窄。如果这些实验成功，我们的计划是开发ATL 146 e/rolipram支架作为新产品。ATL 146 e和咯利普兰都被批准用于人体，腺苷治疗公司已经为这些化合物的联合使用颁发了专利，以防止再狭窄。目的1：研究ATL 146 e和咯利普兰从支架中洗脱到血液中的体外动力学。为此，我们还将使用静脉内给药后从猪血液中提取的化合物的液相色谱/质谱法测定ATL 146 e和咯利普兰在猪中的终末分布半衰期。基于这些数据，我们将在支架上装载足以达到仅1 ng/kg游离血液浓度的化合物，这不太可能产生副作用。目的2提出检查猪中装载有ATL 146 e +/-咯利普兰的支架的再狭窄。将结果与含有西罗莫司作为金标准的市售支架进行比较。由于ATL 146 e和咯利普兰均已获批用于人体，我们预计，如果本研究的结果表明ATL 146 e +/-咯利普兰比西罗莫司更有效，则有可能启动II期临床试验，以在人体中测试ATL 146 e/咯利普兰支架。

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.