From lead to preclinical candidate: optimization of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV.
A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.
Nordhoff
Sonja
S
Santhera Pharmaceuticals (Switzerland) Ltd, Hammerstrasse 47, CH-4410 Liestal, Switzerland. sonja.nordhoff@santhera.com
López-Canet
Meritxell
M
Hoffmann-Enger
Barbara
B
Bulat
Stephan
S
Cerezo-Gálvez
Silvia
S
Hill
Oliver
O
Rosenbaum
Claudia
C
Rummey
Christian
C
Thiemann
Meinolf
M
Matassa
Victor G
VG
Edwards
Paul J
PJ
Feurer
Achim
A
D000284:Administration, Oral; D000613:Aminobutyrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000613:Aminobutyrates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006845:Hydrocarbons, Fluorinated; D007004:Hypoglycemic Agents; D011480:Protease Inhibitors; D011759:Pyrrolidines; C014328:2-amino-4-phenylbutyric acid; D018819:Dipeptidyl Peptidase 4