Discovery of 3-aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors.
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
Cox
Jason M
JM
Merck Research Laboratories, Department of Medicinal Chemistry, PO Box 2000, Rahway, NJ 07065, USA. jason_cox@merck.com
Harper
Bart
B
Mastracchio
Anthony
A
Leiting
Barbara
B
Sinha Roy
Ranabir
R
Patel
Reshma A
RA
Wu
Joseph K
JK
Lyons
Kathryn A
KA
He
Huaibing
H
Xu
Shiyao
S
Zhu
Bing
B
Thornberry
Nancy A
NA
Weber
Ann E
AE
Edmondson
Scott D
SD
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010880:Piperidines / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010880:Piperidines