dipeptidyl peptidase-4 inhibitors: a systematic review of structure-activity relationship studies

Context: dipeptidyl peptidase 4 (dpp-4) is a serine exopeptidase enzyme that hydrolyzes the amide bond at the n-terminal of peptides. this enzyme converts incretins, such as glucagon-like peptide i and glucose-dependent insulinotropic peptide, into their inactive forms, thereby preventing them from stimulating insulin secretion. numerous studies have confirmed the role of dpp-4 in the pathophysiology of type 2 diabetes, leading to the development of various dpp-4 inhibitors. in recent years, research on dpp-4 inhibitors has expanded significantly, resulting in the creation of both non-peptidomimetic heterocyclic compounds and peptidomimetic scaffolds. evidence acquisition: this systematic review summarizes all recent advances related to dpp-4 inhibitors up to 2024. it begins by outlining the biochemical characteristics of dpp-4 and general pharmacological principles of dpp-4 inhibition, followed by an overview of the latest developments from recent publications. the review provides valuable insights into the pharmacophores necessary for ligand-protein interactions, aimed at understanding the structure-activity relationship of novel dpp-4 inhibitors. data for this review was collected from sources including sciencedirect, pubmed, and scopus. results: this review highlights various chemical scaffolds that have been explored in the development of novel dpp-4 inhibitors. it emphasizes scaffolds with significant dpp-4 inhibitory activity, including azoles, azines, sulfonamides, and quinolone motifs. the article also details the structure-activity relationships of newly developed analogs, providing a comprehensive overview of recent advancements in this area. conclusions: despite moderate progress in the development of novel dpp-4 inhibitors, emerging molecular aspects of dpp-4 intervention show great promise for future therapeutic developments.