Discovery of potent, selective, and orally bioavailable pyridone-based dipeptidyl peptidase-4 inhibitors.
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. The optimized compound exhibited good pharmacokinetic profiles in three preclinical species.
Xu
Jinyou
J
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Jinyou_Xu@merck.com
Wei
Lan
L
Mathvink
Robert
R
Edmondson
Scott D
SD
Mastracchio
Anthony
A
Eiermann
George J
GJ
He
Huaibing
H
Leone
Joseph F
JF
Leiting
Barbara
B
Lyons
Kathryn A
KA
Marsilio
Frank
F
Patel
Reshma A
RA
Petrov
Aleksandr
A
Wu
Joseph K
JK
Thornberry
Nancy A
NA
Weber
Ann E
AE
D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000577:Amides / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004285:Dogs; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D058892:Adenosine Deaminase Inhibitors; D000577:Amides; D006023:Glycoproteins; D011480:Protease Inhibitors; D011728:Pyridones; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; D009584:Nitrogen