4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV.
A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
Kaelin
David E
DE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. david_kaelin@merck.com
Smenton
Abigail L
AL
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
Duffy
Joseph L
JL
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D054873:Dipeptidyl-Peptidase IV Inhibitors; D051379:Mice; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D000409:Alanine