The long march towards testing the adenosine receptor agonism hypothesis for human cerebroprotection: The story of the A1R/A3R receptor agonist AST-004

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AST-004 is an adenosine A 1 R/A 3 R agonist and promising cerebroprotectant currently in Phase II clinical development. Clinical evaluations have been initiated in concussion, with trials in preparation for mild complicated traumatic brain injury (TBI) and acute ischemic stroke (AIS). AST-004 was discovered as the result of basic research on the P2Y 1 R-activated homeostatic roles of astrocytes in cerebroprotection, including control of edema, excitotoxicity and oxidative stress. AST-004 was identified as the active nucleoside metabolite of the P2Y 1 R agonist MRS2365. Subsequent research demonstrated that astrocyte mitochondrial ATP production could be activated by AST-004, resulting in significant efficacy in rodent models of permanent and transient occlusion AIS, porcine models of TBI and a non-human primate model of AIS as well as models of neurodegeneration and addiction. The purpose of this review is to highlight the research that led to the discovery of AST-004, summarize its widespread preclinical efficacy in a variety of disease models, and describe how this compound’s excellent safety and pharmaceutical profile is differentiated from prototypical A 1 R and A 3 R agonists formerly or currently in the clinic.