Dipeptidyl peptidase IV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes.
Glucagon-like peptide-1 (GLP-1 (7-36) amide) is a gut hormone released from L-cells in the small intestine in response to the ingestion of nutrients and enhances the glucose-dependent secretion of insulin from pancreatic beta-cells. In type 2 diabetic patients, the continuous infusion of GLP-1 (7-36) amide decreases plasma glucose and hemoglobin A1c concentrations and improves beta-cell function. Hormone action is rapidly terminated by the N-terminal cleavage of GLP-1 at Ala2 by the aminopeptidase, dipeptidyl peptidase IV (DPPIV). The short in vivo half-life of GLP-1 (< 3 min) poses challenges to the development of exogenous GLP-1-based therapy. The inhibition of endogenous GLP-1 degradation by reducing DPPIV activity is an alternative strategy for improving the incretin action of GLP-1 in vivo. This review summarizes recent advances in the design of potent and selective small molecule inhibitors of DPPIV and the potential challenges to the development of DPPIV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes.
Wiedeman
Paul E
PE
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. paul.e.wiedeman@abbott.com
Trevillyan
James M
JM
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000502:physiology*; D015195:Drug Design; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000627:therapeutic use
D007004:Hypoglycemic Agents; D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; C032519:pyrrolidine