Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV.
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.
Feng
Jun
J
Zhang
Zhiyuan
Z
Wallace
Michael B
MB
Stafford
Jeffrey A
JA
Kaldor
Stephen W
SW
Kassel
Daniel B
DB
Navre
Marc
M
Shi
Lihong
L
Skene
Robert J
RJ
Asakawa
Tomoko
T
Takeuchi
Koji
K
Xu
Rongda
R
Webb
David R
DR
Gwaltney
Stephen L
SL
D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D065607:Cytochrome P-450 Enzyme Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005260:Female; D005951:Glucose Tolerance Test; D000882:Haplorhini; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D001786:Blood Glucose; D065607:Cytochrome P-450 Enzyme Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007004:Hypoglycemic Agents; D010880:Piperidines; D011744:Pyrimidinones; D052999:Quinazolinones; D014498:Uracil; D018819:Dipeptidyl Peptidase 4; C520853:alogliptin