Rapid generation of a novel DPP-4 inhibitor with long-acting properties: SAR study and PK/PD evaluation

Drug compliance is critical for patients with chronic diseases such as diabetes. In our continuous effort to find better glucose-lowering agents, an exploration for long-acting DPP-4 inhibitors had been launched. Based on our previously reported compounds bearing a pyrrolopyrimidine scaffold, the lead compound 4a (IC50 = 2.3 nM, t1/2(rat) = 5.46 h) with pharmacokinetic superiority was rapidly determined. Further SAR study indicated that the pyrrole ring was generally tolerable for variation, in which a β-substitution gave a better DPP-4 affinity. In depth evaluation of the pyrrole ring β position identified a highly potent compound 12a (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). In vivo pharmacodynamics tests demonstrated similar or even slightly better sustained DPP-4 inhibition for compounds 4a and 12a compared with the first marketed once-weekly drug trelagliptin in this category, indicating that improvements to DPP-4 inhibitory activity or pharmacokinetic profile might be feasible ways to rapidly generate long-acting DPP-4 inhibitors. Compound 12a with an IC50 of 0.76 nM and competent in vivo efficacy with trelagliptin. [Display omitted] •Novel DPP-4 inhibitors with long-acting property were rapidly generated.•Compound 12a with an IC50 of 0.76 nM displayed a competent in vivo efficacy with once-weekly trelagliptin.•Fine PK property and strong affinity might contributed to the long-acting of xanthine based DPP-4 inhibitors.