Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels due to insufficient insulin production or ineffective utilization, with two main types: type 1 requiring external insulin administration and type 2 managed through medications, diet changes, and physical activity [1]. Diabetes can cause a variety of complications, including affecting the musculoskeletal system [2,3]. Diabetes increases the risk of osteoporosis, fractures (especially in the hip, wrist, and spine), arthritis (particularly osteoarthritis of the hands and knees), and foot complications.

Dipeptidyl Peptidase-4 (DPP-4), a crucial enzyme involved in the regulation of glucose metabolism, plays a pivotal role in the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). These gut-derived hormones are released upon food intake [1,4,5]. Inhibition of DPP-4 activity leads to elevated levels of these hormones, thereby promoting increased insulin secretion and suppression of glucagon release, ultimately resulting in enhanced glycemic control. DPP-4 inhibitors have revolutionized T2DM treatment, potentially preventing complications like osteoporosis, fractures, and foot issues. These inhibitors exert their function by inhibiting the enzymatic activity of DPP-4, thereby prolonging the half-life of GLP-1 and GIP. Consequently, enhanced insulin secretion from pancreatic β cells in response to glucose levels is observed, while glucagon release from α cells is reduced. This overall effect leads to improved regulation of blood sugar levels and a decreased risk of hypoglycemia compared to alternative antidiabetic medications [6,7].

Since the approval of Sitagliptin, the first DPP-4 inhibitor, in 2006, several other small-molecule inhibitors have been developed and are currently available for clinical use [8], including Vildagliptin, Saxagliptin, Linagliptin, and Alogliptin. Each of these inhibitors possesses a distinct chemical structure and pharmacokinetic profile that significantly influences their efficacy, safety, and dosing requirements [9]. The synthesis of DPP-4 inhibitors entails the design and optimization of small molecules capable of selectively binding to the enzyme's active site. Structure-activity relationship (SAR) studies have played a pivotal role in identifying crucial molecular characteristics necessary for the potent inhibition of DPP-4 [[10], [11], [12], [13]]. These studies have led to the development of highly selective and potent inhibitors with improved pharmacokinetic properties, which exhibit enhanced glucose-lowering effects. Moreover, DPP-4 inhibitors have demonstrated pleiotropic effects that may confer additional benefits in the management of T2DM, encompassing enhancements in beta-cell function, preservation of pancreatic islet mass, reduction in oxidative stress and inflammation, as well as potential cardiovascular advantages. These pleiotropic effects are believed to be mediated through both GLP-1-dependent and GLP-1-independent mechanisms [[14], [15], [16], [17]].

The progress achieved in the field of DPP-4 inhibitors research holds significant promise for diversifying therapeutic strategies in T2DM therapy (Table 1 and Fig. 1). However, it is crucial to emphasize the need for continuous and thorough investigation to fully explore the potential inherent in these inhibitors. An exploration of the intricate synthetic methodologies employed at various stages in developing DPP-4 inhibitors, along with their corresponding mechanisms of action within clinical contexts, has substantial potential to catalyze the advancement of innovative pharmaceutical agents for T2DM therapy. These findings presented herein hold considerable significance, particularly in shaping future drug design endeavors.