Pharmacological profile of ASP8497, a novel, selective, and competitive dipeptidyl peptidase-IV inhibitor, in vitro and in vivo.

Dipeptidyl peptidase (DPP)-IV is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibitors are expected to become a useful new class of antidiabetic agent. This report describes the pharmacological profile of the novel DPP-IV inhibitor, ASP8497 [(2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate], both in vitro and in vivo. ASP8497 inhibited DPP-IV in plasma from mice, dogs, and humans with median inhibition concentration (IC(50)) values of 2.6 nM, 7.3 nM, and 6.2 nM, respectively. In contrast, ASP8497 did not potently inhibit human DPP8 or DPP9 activity (IC(50)=1,700 nM and 100 nM, respectively) and exhibited selectivity against several proteases, including proline-specific proteases (IC(50)>10 microM). Kinetic analysis indicated that ASP8497 is a competitive DPP-IV inhibitor. In normal mice, ASP8497 inhibited plasma DPP-IV activity even 12 h after administration. ASP8497 significantly inhibited increases in the blood glucose level during the oral glucose tolerance test (OGTT) conducted 0.5 h after administration. This was accompanied by increases in the plasma active GLP-1 and insulin levels. In addition, ASP8497 significantly inhibited increases in the blood glucose level during the OGTT conducted 8 h after administration. Furthermore, in Zucker fatty rats, ASP8497 dose dependently improved glucose tolerance with significance at doses of 1 mg/kg or higher. In contrast, ASP8497 did not cause hypoglycemia in fasted normal mice. These results indicate that ASP8497 is a potent, competitive, and selective DPP-IV inhibitor with antihyperglycemic activity.