4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV.
A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.
Duffy
Joseph L
JL
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
Kirk
Brian A
BA
Wang
Liping
L
Eiermann
George J
GJ
He
Huaibing
H
Leiting
Barbara
B
Lyons
Kathryn A
KA
Patel
Reshma A
RA
Patel
Sangita B
SB
Petrov
Alexsandr
A
Scapin
Giovanna
G
Wu
Joseph K
JK
Thornberry
Nancy A
NA
Weber
Ann E
AE
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C521364:4-aminocyclohexylalanine; D003510:Cyclohexanes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; C009722:4-aminophenylalanine; D010649:Phenylalanine; D018819:Dipeptidyl Peptidase 4; D000409:Alanine