1.Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors.
Jiang T1, Zhou Y1, Zhu J1, Chen Z1, Sun P1, Zhang Q1, Wang Z1, Shao Q1, Jiang X1, Li B1, Wang H1, Zhu W1, Shen J1. Arch Pharm (Weinheim). 2015 Jun;348(6):399-407. doi: 10.1002/ardp.201500082. Epub 2015 Apr 14.
The optimization of a series of fused β-homophenylalanine inhibitors of dipeptidyl peptidase-4 (DPP-4) is described. Modification on the P2-binding moiety of 6 (IC50 = 10 nM) led to the discovery of β-homophenylalanine derivatives containing pyrrolidin-2-ylmethyl amides. The introduction of a sulfamine in the meta position of the phenyl ring improved the potency against DPP-4 (6-12-fold increase). Compound 14k showed DPP-4 inhibitory activity with an IC50 value of 0.87 nM. Meanwhile, in vivo experiments exhibited that 14h had an efficiency comparable to sitagliptin at the dose of 10 mg/kg.