The design of potent and selective inhibitors of DPP-4: optimization of ADME properties by amide replacements.
For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
Nordhoff
Sonja
S
Santhera Pharmaceuticals (Switzerland) Ltd, Hammerstrasse 47, CH-4410 Liestal, Switzerland. sonja.nordhoff@santhera.com
Bulat
Stephan
S
Cerezo-Gálvez
Silvia
S
Hill
Oliver
O
Hoffmann-Enger
Barbara
B
López-Canet
Meritxell
M
Rosenbaum
Claudia
C
Rummey
Christian
C
Thiemann
Meinolf
M
Matassa
Victor G
VG
Edwards
Paul J
PJ
Feurer
Achim
A
D000577:Amides / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000613:Aminobutyrates / Q000737:chemistry*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D000613:Aminobutyrates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011480:Protease Inhibitors; D015222:Sodium Channels; C014328:2-amino-4-phenylbutyric acid