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Design, Synthesis, and Pharmacological Evaluation of Highly Potent and Selective Dipeptidyl Peptidase‐4 Inhibitors
Author(s) -
Jiang Tao,
Zhou Yuren,
Zhu Jianming,
Chen Zhuxi,
Sun Peng,
Zhang Qiang,
Wang Zhen,
Shao Qiang,
Jiang Xiangrui,
Li Bo,
Wang Heyao,
Zhu Weiliang,
Shen Jingshan
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500082
Subject(s) - chemistry , dipeptidyl peptidase , dipeptidyl peptidase 4 , enzyme inhibitor , pharmacology , chemical synthesis , combinatorial chemistry , enzyme , biochemistry , stereochemistry , biology , in vitro , diabetes mellitus , type 2 diabetes , endocrinology
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 (IC 50 = 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 IC 50 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.