Dipeptidyl peptidase 4 (DPP-4), a substrate-specific serine protease, has been validated as a promising drug target for the
treatment of type 2 diabetes. DPP-4 inhibitors significantly lowered blood glucose levels in patients with type 2 diabetes without common
body weight gain, hypoglycemia and gastrointestinal disturbance side effects. Therefore, DPP-4 inhibitors attracted more and more
attention. In particular, non-peptidomimetic DPP-4 inhibitors have been a focus of research and development and made great progress in
recent years, which resulted in the discovery of a wide variety of potent non-peptidomimetic DPP-4 inhibitors. Some of them, such as
sitagliptin, alogliptin and linagliptin have already been used as marketed drugs, while others have been into clinical trials. Based on the
core structural features of non-peptidomimetic DPP-4 inhibitors, seven types were classified in the article. For each type, we focused on
the description of strategies for design and optimization, together with a discussion on concluded structure-activity relationships (SAR).
In addition, the contribution of specific substituents to the inhibition of DPP-4 was summarized. Selectivity towards the inhibition of
DPP-4 over dipeptidyl peptidase 8 (DPP-8) and dipeptidyl peptidase 9 (DPP-9) was also presented.
Keywords: Analogs, DPP-4, drug design, inhibitors, medicinal chemistry, non-peptidomimetic, preclinical, SAR, selectivity, type 2 diabetes
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