EVOLUTION AND FUTURE PROSPECTS OF HETEROCYCLIC SCAFFOLDS IN DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS: A MEDICINAL CHEMISTRY PERSPECTIVE

Dipeptidyl peptidase-4 (DPP-4) inhibitors, or gliptins, represent a cornerstone in the oral management of Type 2 Diabetes Mellitus (T2DM). Their mechanism, which potentiates endogenous incretin hormones, offers glucose-dependent efficacy with a minimized risk of hypoglycemia. The discovery and optimization of these agents are inextricably linked to the strategic deployment of heterocyclic chemistry. This review provides a critical analysis of the pivotal role heterocyclic scaffolds play in DPP-4 inhibitor design, from first-in-class drugs to next-generation candidates. We begin by elucidating the structural biology of DPP-4, detailing the catalytic triad (Ser630, Asp708, His740) and the key sub-pockets (S1, S2, S2 extensive) that serve as a blueprint for rational inhibitor design. A retrospective analysis of clinically approved gliptins including sitagliptin (pyrazolopyrimidine), saxagliptin (constrained cyanopyrrolidine), linagliptin (xanthine), and alogliptin (pyrimidinedione)-highlights how specific heterocyclic cores dictate potency, selectivity, and pharmacokinetic profiles. The core of this review surveys recent advances (2012–present) in novel heterocyclic chemotypes explored as DPP-4 inhibitors. We systematically categorize and discuss promising scaffolds such as pyrimidines, oxadiazoles, pyrrolidines, triazoles, triazines, piperazines, quinazolines, pyrazoles, and indolines, emphasizing structure-activity relationship (SAR) insights, computational modeling approaches, and in-vitro/in-vivo results. Finally, we examine the current clinical pipeline and future perspectives, addressing challenges like long-term safety and the pursuit of multi-target agents or once-weekly formulations. The integration of advanced computational tools, fragment-based design, and personalized medicine principles is poised to guide the development of next-generation heterocyclic DPP-4 inhibitors with enhanced therapeutic profiles.