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Abstract

Grant Number:	5R42AI046852-03
PI Name:	THOMPSON, ROBERT D.
PI Email:	rdt@adenrx.com
PI Title:	INTERIM DIRECTOR OF CHEMISTRY
Project Title:	A2a Adenosine Agonists Limit Damage from Infection

Abstract: DESCRIPTION (Provided by applicant): Sepsis syndrome is the 11th leading cause of death in the United States ( about 900,000 new cases per year) with a mortality of about 35 percent. The need for adjunctive therapies is urgent. In Phase I of this SBIR award we documented the anti-inflammatory effects of adenosine A2A receptor (A2AAR) agonists on isolated immune cells and have observed dramatically improved survival in mouse models of Iipopolysaccaride-and live E. coli-induced septic shock. Screening 30 newly-synthesized A2AAR agonists showed that the prototype, ATL146e, remained the most potent, selective and least likely to have toxic metabolites. In phase II we propose additional studies on ATL146e aiming at an IND application. Aim 1 will characterize the acute, single-dose toxicology, pharmacokinetics and metabolism of ATL146e. Aim 2 will develop methods for the scale-up of the synthesis of 2-iodoNECA, the key intermediate in the synthesis of ATL146e, and will characterize its stability, solubility and formulation. Aim 3 will optimize treatment regimens with ATL146e in a mouse model of E. coli peritonitis and bacteremia. Aim 4 examines the effect of treatment with ATL146e on end points other than mortality, namely dysfunction of liver, kidney and lung, as well as on cytokine responses that could be useful in patient monitoring. PROPOSED COMMERCIAL APPLICATION: Only one product, Activated Protein C, is expected to reach the market with an indication to treat sepsis. Clinical studies, however, have demonstrated that only one life was saved for every 16 treated. Additional options for treatment are urgently required to address this unmet medical need. A pharmaceutical product that contains an A2A agonist as the active ingredient would be a very valuable addition to the physician's armament in fighting sepsis and is the goal of this research.

Thesaurus Terms:
adenosine, antiinfective agent, antiinflammatory agent, drug design /synthesis /production, purinergic receptor, stimulant /agonist
Escherichia coli, antibiotic, bacterial disease, blood toxicology, inflammation, peritonitis, pharmacokinetics, receptor binding
laboratory mouse

Institution:	ADENOSINE THERAPEUTICS, LLC
	300 PRESTON AVE, 5TH FL
	CHARLOTTESVILLE, VA 22902
Fiscal Year:	2003
Department:
Project Start:	01-AUG-2000
Project End:	30-APR-2004
ICD:	NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
IRG:	ZRG1

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