Inhibitors of dipeptidyl peptidase‐4 as therapeutic agents for individuals with type 2 diabetes: a 25‐year journey

In the 25 years since the hypothesis was first described, therapeutic use of inhibitors of dipeptidyl peptidase‐4 (DPP‐4i) as a novel approach to the treatment of type 2 diabetes has become established widely, with several compounds now available to exemplify the class. Although the clinical profiles of members of the DPP‐4i class have been reviewed extensively, the underlying pragmatic small molecular design and pharmaceutical properties of these agents have seldom been addressed in the context of establishment of the class as treatments for type 2 diabetes. Among the reasons contributing to the wide acceptance of DPP‐4i as oral anti‐hyperglycaemic therapy are: (i) the endocrine basis of their pharmacology; (ii) their chemical ‘simplicity’ and low molecular mass; (iii) their pharmacological selectivity for their target mechanism of action; (iv) the nature of physiologically relevant substrates for the enzyme; (v) their relative ease of formulation into tablets; (vi) their efficacy as glucose‐lowering agents; (vii) their absorption, distribution, metabolism and elimination profiles; and (viii) their limited tolerability issues. What’s new? This is an intentionally brief review highlighting aspects of the design of dipeptidyl peptidase‐4 (DPP‐4) inhibitors that are often overlooked in more conventional reviews. It has been written primarily with the purpose of informing primary care healthcare professionals. The review focuses upon how the pharmacology and some properties of small molecules have facilitated the successful development of therapeutic agents. The review is timely because it is now 25 years since the hypothesis to treat type 2 diabetes with inhibitors of DPP‐4 was first described in the literature. The chemical and pharmacological properties of DPP‐4 inhibitor drugs that make them suitable for oral therapy of type 2 diabetes are discussed. Features distinguishing small molecules from biotechnological alternatives are reviewed briefly.