Recent Advances in Non-Peptidomimetic Dipeptidyl Peptidase 4 Inhibitors: Medicinal Chemistry and Preclinical Aspects

Abstract

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.

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

“…Additionally, some authors have assigned Val207, Ser209, Phe357, and Arg358 to a site beyond S 2 where the inhibitors but not the substrates can bind well to increase their inhibitory activity and which has been termed either the S 2 extensive subsite or the S 3 pocket . Nevertheless, in line with most authors we have assigned Ser209, Phe357, and Arg358 to the S 2 subsite (although throughout this review we also sometimes use the term S 2 extensive subsite to refer collectively to these three residues).…”

“…In the last decade, many reviews focusing on DPP‐IV inhibitors have been published . Some of these address a wide range of topics such as the incretin system and incretin mimetics, DPP‐IV inhibitor selectivity and the implications of DPP‐IV inhibition, and even structure optimization in the search for chemical stability, selectivity, and favorable pharmacokinetic properties .…”

“…Some of these address a wide range of topics such as the incretin system and incretin mimetics, DPP‐IV inhibitor selectivity and the implications of DPP‐IV inhibition, and even structure optimization in the search for chemical stability, selectivity, and favorable pharmacokinetic properties . Most of them devote a major part of their content to classifying DPP‐IV inhibitors by structure, listing their activities, and their pharmacokinetic and toxicological properties, describing the binding mode of different inhibitor types, specifying which moieties interact with different DPP‐IV subsites and reporting how changes in their substituents affect their bioactivity …”

The pathological significance of dipeptidyl peptidase-4 in endothelial cell homeostasis and kidney fibrosis

“…(i) DPP-4 inhibitors can be divided on the basis of their structure into those that mimic the dipeptide structure of DPP-4 substrates and those that are nonpeptidomimetic. Sitagliptin belongs to the peptidomimetic family, which exhibits a triazolopiperazine-based structure, and linagliptin belongs to the nonpeptidomimetic family, which includes imidazolebased inhibitors [85,86]. (ii) Linagliptin is likely lipophilic [87].…”

DPP-4 inhibitors: a patent review (2012 – 2014)

“…Different models confirm that the presence of a primary amine, an aromatic ring and a variable substituent are essential on the core scaffold. The S2 pocket is responsible for the inhibitor selectivity on DPP-4 over DPP-8 and DPP-9 ( Figure 2); in fact, residues Glu 205 and Glu 206 of S2 pocket are involved in salt bridge interactions with cationic groups [24].…”