Discovery and structure-activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors.
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
Pei
Zhonghua
Z
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. zhonghua.pei@abbott.com
Li
Xiaofeng
X
von Geldern
Thomas W
TW
Longenecker
Kenton
K
Pireh
Daisy
D
Stewart
Kent D
KD
Backes
Bradley J
BJ
Lai
Chunqiu
C
Lubben
Thomas H
TH
Ballaron
Stephen J
SJ
Beno
David W A
DW
Kempf-Grote
Anita J
AJ
Sham
Hing L
HL
Trevillyan
James M
JM
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008968:Molecular Conformation; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D010627:Phenethylamines; D010880:Piperidines; D010881:Piperidones; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4