Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke.

BACKGROUND AND PURPOSE: Treatment with A1R/A3R (adenosine A1 and A3 receptor) agonists in rodent models of acute ischemic stroke results in significantly reduced lesion volume, indicating activation of adenosine A1R or A3R is cerebroprotective. However, dosing and timing required for cerebroprotection has yet to be established, and whether adenosine A1R/A3R activation will lead to cerebroprotection in a gyrencephalic species has yet to be determined. METHODS: The current study used clinical study intervention timelines in a nonhuman primate model of transient, 4-hour middle cerebral artery occlusion to investigate a potential cerebroprotective effect of the dual adenosine A1R/A3R agonist AST-004. Bolus and then 22 hours intravenous infusion of AST-004 was initiated 2 hours after transient middle cerebral artery occlusion. Primary outcome measures included lesion volume, lesion growth kinetics, penumbra volume as well as initial pharmacokinetic-pharmacodynamic relationships measured up to 5 days after transient middle cerebral artery occlusion. Secondary outcome measures included physiological parameters and neurological function. RESULTS: Administration of AST-004 resulted in rapid and statistically significant decreases in lesion growth rate and total lesion volume. In addition, penumbra volume decline over time was significantly less under AST-004 treatment compared with vehicle treatment. These changes correlated with unbound AST-004 concentrations in the plasma and cerebrospinal fluid as well as estimated brain A1R and A3R occupancy. No relevant changes in physiological parameters were observed during AST-004 treatment. CONCLUSIONS: These findings suggest that administration of AST-004 and combined A1R/A3R agonism in the brain are efficacious pharmacological interventions in acute ischemic stroke and warrant further clinical evaluation.

Reduction of free fatty acids, safety, and pharmacokinetics of oral GS-9667, an A(1) adenosine receptor partial agonist.

GS-9667, a new selective, partial agonist of the A(1) adenosine receptor (AR), may represent an effective therapy for Type 2 diabetes (T2DM) and dyslipidemia via lowering of free fatty acids (FFA). The objectives of the studies were to evaluate the effects of single and multiple doses of GS-9667 on plasma FFA concentrations, its pharmacokinetics (PK) and safety/tolerability. Two studies were conducted. In the single ascending dose study, healthy, non-obese, and obese subjects received a single oral dose of GS-9667 (30-1,800 mg). In the multiple, ascending dose study, healthy, obese subjects received GS-9667 (600-2,400 mg QD, 1,200 mg BID, or 600 mg QID) for 14 days. Blood and urine samples were collected for lipid profiling and PK analyses. The ECG, vital signs, and subject tolerability were monitored. Doses of GS-9667 ≥300 mg caused dose-dependent reductions in FFA levels that were reproducible over 14 days without evidence of desensitization or rebound. All doses were well tolerated. GS-9667 was rapidly absorbed and distributed; Steady-state concentrations were achieved within 3-5 days. The A(1) AR partial agonist GS-9667 reduced plasma FFA, exhibited linear kinetics, and was well-tolerated in healthy non-obese and obese subjects.