A2A ADENOSINE AGONIST ADJUNCT FOR SYSTEMIC ANTHRAX

DESCRIPTION (provided by applicant): This project develops A2A adenosine receptor (A2AAR) agonists as adjuncts to antibiotics for the treatment of anthrax septicemia. It responds to the urgent need for better treatment of highly lethal infections by this bioterrorism/biowarfare agent. Phase I has two aims, pharmaceutical development and documentation of efficacy in clinically relevant settings. The goal of Aim I is to identify one lead and two to three backup compounds for development. It applies USP criteria to the screening of the company library of 50 proprietary A2AAR agonists for pharmaceutically relevant factors such as in vitro efficacy, solubility, stability to heat, light and pH, followed by secondary screens to document physical characteristics such as pKa, hydrophobicity and affinity for plasma proteins. The goal of Aim 2 is to demonstrate preliminary efficacy. It develops a mouse model of anthrax toxin sepsis by: (1) dose-ranging studies on anthrax lethal toxin (LT); (2) dose-ranging studies of A2AAR agonist protection against LT sepsis; (3) studies of the effect of delay in administration of A2AAR agonist on protection against LT sepsis, and (4) documentation that the A2AAR specifically mediates the protective effect of these agonists. Attaining both aims will argue for continuing on to Phase II for additional assessments of efficacy as well as of pharmacokinetics and metabolism.