Novel A2A Adenosine Agonists in Vascular Protection

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.