SBIR-STTR Award

This is a phase I SBIR proposal by Adenosine Therapeutics for 6 months of support to synthesize and evaluate novel compounds as agonists of equine A2A adenosine receptors. APPROACH: At the University of Georgia, Tom Murray, PhD has recently succeeded in cloning the equine A2A adenosine receptor, and James Moore, PhD is a leading authority on the study of equine sepsis. This proposal is a joint venture between Adenosine Therapeutics and the University of Georgia to synthesize and evaluate A2A agonist compounds for (1) binding to recombinant equine A2A adenosine receptors; (2) function as assessed by their ability to inhibit TNF release from equine monocytes; and (3) duration of action as assessed by persistence of vasocillator action in rats. An optimal compound based on high potency and long duration of action will be selected as a therapeutic candidate and evaluated for its ability to reduce markers of inflammation in horses treated with endotoxin. NON-TECHNICAL SUMMARY: This is a phase I SBIR proposal by Adenosine Therapeutics for 6 months of support to synthesize and evaluate novel compounds as agonists of equine A2A adenosine receptors. Some of these compounds have been found to be very effective in reducing rodent mortality form endotoxin or from E. coli-induced sepsis. Circulating endotoxin (lipopolysaccharide) is correlated with the probability of death in horses of all ages (colic in adult horses; septicemia in neonates). These studies have the potential of producing a new therapy of horse sepsis and colic that are devastating equine diseases. Our goal is to develop new therapies for the treatment of equine sepsis and colic. Such new therapies have excellent commercial potential since these diseases occur in tens of thousands of horses annually and these animals have a poor prognosis. Preliminary studies in rodents indicate that this new type of therapy is highly effective in reducing the severity of septic inflammation and drastically reduces the frequency of mortality.

Keywords:
colic; sepsis; endotoxin; lipopolysaccharide; adenosine; a2a adenosine receptor

Endotoxemia (Sepsis) affects horses of all breeds and ages and is the leading causes of death in adult horses and foals. Consequently, its economic impact on the equine industry in the United States is devastating. This project seeks to develop new treatments for this disease. OBJECTIVES: Endotoxemia is associated with the leading causes of death in horses and foals, and has a huge economic impact on the US equine industry. The deleterious effects of endotoxin are due to pro-inflammatory mediators released by the horses white blood cells, and current methods of treatment fail to adequately modulate production of these mediators. Based on recent studies showing that adenosine A2A receptor agonists protect laboratory animals against lethal effects of endotoxins, in Phase I we showed that A2A receptor agonists synthesized by Adenosine Therapeutics avidly bind equine A2A receptors, significantly reduce the pro-inflammatory effects of endotoxin in vitro, and exert these anti-inflammatory effects at remarkably low dosages. APPROACH: This Phase II study proposes to address the following objectives: 1) Screen newly synthesized A2A agonists for receptor binding selectivity and anti-inflammatory effects, and scale-up synthesis of selected agonists for administration to horses, 2) Perform in vivo studies to identify dosages that can be administered safely to horses, 3) Determine the duration of anti-inflammatory effects, and 4) Test the most selective and longest acting compound in an in vivo model of equine endotoxemia. Successful completion of these studies will provide the basis for a new efficacious method of treating endotoxemia in horses.