Abstract
Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.
Publication types
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Binding Sites
-
Blood Glucose / analysis
-
Cytochrome P-450 Enzyme Inhibitors
-
Diabetes Mellitus, Experimental / drug therapy
-
Dipeptidyl Peptidase 4 / chemistry*
-
Dipeptidyl-Peptidase IV Inhibitors*
-
Dogs
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels / drug effects
-
Female
-
Glucose Tolerance Test
-
Haplorhini
-
Humans
-
Hypoglycemic Agents / chemical synthesis*
-
Hypoglycemic Agents / pharmacokinetics
-
Hypoglycemic Agents / pharmacology
-
In Vitro Techniques
-
Mice
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Piperidines / chemical synthesis*
-
Piperidines / pharmacokinetics
-
Piperidines / pharmacology
-
Pyrimidinones / chemical synthesis*
-
Pyrimidinones / pharmacokinetics
-
Pyrimidinones / pharmacology
-
Quinazolinones / chemical synthesis*
-
Quinazolinones / pharmacokinetics
-
Quinazolinones / pharmacology
-
Rats
-
Rats, Wistar
-
Structure-Activity Relationship
-
Uracil / analogs & derivatives*
-
Uracil / chemical synthesis
-
Uracil / pharmacokinetics
-
Uracil / pharmacology
Substances
-
Blood Glucose
-
Cytochrome P-450 Enzyme Inhibitors
-
Dipeptidyl-Peptidase IV Inhibitors
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels
-
Hypoglycemic Agents
-
Piperidines
-
Pyrimidinones
-
Quinazolinones
-
Uracil
-
Dipeptidyl Peptidase 4
-
alogliptin