Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes

Emerging as an epidemic of the 21st century type 2 diabetes has become a major health problem throughout the globe. The number of deaths attributable to diabetes reflects the insufficient glycemic control achieved with the treatments used in recent past. DPP-4 inhibitors have been investigated as a new therapy with novel mechanisms of action and improved tolerability. DPP-4, a protease that specifically cleaves dipeptides from proteins and oligopeptides after a penultimate N-terminal proline or alanine, is involved in the degradation of a number of neuropeptides, peptide hormones and cytokines, including the incretins GLP-1 and GIP. As soon as released from the gut in response to food intake, GLP-1 and GIP exert a potent glucose-dependent insulinotropic action, thereby playing a key role in the maintenance of post-meal glycemic control. Consequently, inhibiting DPP-4 prolongs the action of GLP-1 and GIP, which in turn improves glucose homeostasis with a low risk of hypoglycemia and potential for disease modi. cation. Indeed, clinical trials involving diabetic patients have shown improved glucose control by administering DPP-4 inhibitors, thus demonstrating the benefit of this promising new class of antidiabetics. Intense research activities in this area have resulted in the launch of sitagliptin and vildagliptin (in Europe only) and the advancement of a few others into preregistration/phase 3, for example, saxagliptin, alogliptin and ABT-279. Achieving desired selectivity for DPP-4 over other related peptidases such as DPP-8 and DPP-9 (inhibition of which was linked to toxicity in animal studies) and long-acting potential for maximal efficacy (particularly in more severe diabetic patients) were the major challenges. Whether these goals are achieved with the present series of inhibitors in the advanced stages of clinical development is yet to be confirmed. Nevertheless, treatment of this metabolic disorder especially in the early stages of the disease via DPP-4 inhibition has been recognized as a validated principle and a large number of inhibitors are presently in various stage of pre-clinical/clinical development. Sitagliptin is a new weapon in the arsenal of oral antihyperglycemic agents. This review will focus on the journey of drug discovery of DPP-4 inhibitors for oral delivery covering a brief scientific background and medicinal chemistry approaches along with the status of advanced clinical candidates. (C) 2009 Elsevier Ltd. All rights reserved.