Dipeptidyl Peptidase-IV Inhibitors: An Evolving Treatment for Type 2 Diabetes from the Incretin Concept

Yau-Jan      Chyan; Lee-Ming      Chuang

doi:10.2174/187221407779814570

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) are the 2 major incretin hormones released after meals to enhance glucose-stimulated insulin secretion. In patients with type 2 diabetes, a loss of activity of GIP for insulinotropic function and a reduced secretion of GLP-1 exist in response to oral glucose while GLP-1 action is preserved. GLP-1 is therefore an attractive avenue for treating type 2 diabetes. Due to the short circulating half-life of GLP-1, which is degraded by dipeptidyl peptidase IV (DPP-IV), 2 approaches have been undertaken. One is to develop long-acting GLP-1 analogs, such as exendin-4 that is resistant to degradation. Here we review another approach for developing DPP-IV inhibitors. This group of potential drugs covers several major chemical classes and their derivatives, such as amino acid amide, carbocyclic, alkylamine, and heterocyclic compounds. More than 100 patents have been issued for DPP-IV inhibitors to be used either as a monotherapy or in combination with other antidiabetic agents for the treatment of type 2 diabetes, as well as metabolic syndrome, osteoporosis, and arthritis. Structure-based drug design is currently under intensive investigation for future development of more selective therapeutic agents.

Keywords: Dipeptidyl peptidase IV, DPP-IV inhibitors, GLP-1, type 2 diabetes

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