Discovery of carmegliptin: a potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.
Mattei
Patrizio
P
F Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland. patrizio.mattei@roche.com
Boehringer
Markus
M
Di Giorgio
Patrick
P
Fischer
Holger
H
Hennig
Michael
M
Huwyler
Joerg
J
Koçer
Buelent
B
Kuhn
Bernd
B
Loeffler
Bernd M
BM
Macdonald
Alexander
A
Narquizian
Robert
R
Rauber
Etienne
E
Sebokova
Elena
E
Sprecher
Urs
U
D000818:Animals; D017322:Clinical Trials, Phase II as Topic; D018360:Crystallography, X-Ray; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D004285:Dogs; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D008252:Macaca fascicularis; D051379:Mice; D011807:Quinolizines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker
D003692:Delayed-Action Preparations; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011807:Quinolizines; C552198:carmegliptin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4