Renal effects of BG9928, an A1 adenosine receptor antagonist, in rats and nonhuman primates

Stimulation of A(1) adenosine receptors in the kidney reduces glomerular filtration rate (GFR) via tubuloglomerular feedback and increases sodium reabsorption. Blocking A(1) adenosine receptors would therefore maintain GFR and cause natriuresis. These attributes would be especially beneficial in treating congestive heart failure (CHF). BG9928 is a xanthine derivative that binds with high affinity to A(1) adenosine receptors from several species including human and acts as a competitive antagonist at these receptors. This compound is being developed for the treatment of CHF. BG9928 receptor binding across a wide array of human and animal receptors was evaluated in vitro. Oral dose-response was assessed in rats, and oral and iv dose-responses were assessed in monkeys. The functional potency of BG9928 was demonstrated in vivo in rats. The binding affinity (K-i) for the human A(1) adenosine receptor is 12.2 nM. BG9928 is orally active, with a dose of 0.3 mg/kg po achieving full natriuretic response in rats and with iv doses as low as 0.03 mg/kg showing activity in nonhuman primates. The renal protective effects of BG9928 were demonstrated by coadministration with the loop diuretic furosemide. In rats, administration of BG9928 effectively attenuated the reductions in GFR that usually occur with the administration of furosemide. Blockade of A(1) receptors by BG9928 protects renal function against the adverse effects of loop diuretics and exerts additive natriuretic effects. In CHF patients, this profile may translate into significant clinical benefit by enhancing natriuresis with diminished concern of inducing renal insufficiency. (C) 2003 Wiley-Liss, Inc.