Synthesis and clinical application of representative small-molecule dipeptidyl Peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus (T2DM).

Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels, which can cause many diseases, including osteoporosis, fractures, arthritis, and foot complications. The inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in glucose metabolism regulation, are essential for managing Type 2 Diabetes Mellitus (T2DM). The inhibition of DPP-4 has become a promising treatment approach for T2DM because it can increase levels of active glucagon-like peptide-1 (GLP-1), leading to improved insulin secretion in response to glucose and reduced release of glucagon. The review commences by elucidating the role of DPP-4 in glucose homeostasis and its significance in T2DM pathophysiology. Furthermore, it presents the mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity profiles of small-molecule DPP-4 inhibitors across various clinical stages. This comprehensive review provides valuable insights into the synthesis and clinical application of DPP-4 inhibitors, serving as an invaluable resource for researchers, clinicians, and pharmaceutical professionals interested in diabetes therapeutics and drug development.