Dipeptidyl peptidase IV inhibitors derived from beta-aminoacylpiperidines bearing a fused thiazole, oxazole, isoxazole, or pyrazole.
A series of beta-aminoacylpiperidines bearing various fused five-membered heterocyclic rings was synthesized as dipeptidyl peptidase IV inhibitors. Potent and relatively selective inhibition could be obtained, depending on choice of heterocycle, regioisomerism, and substitution. In particular, one analog (74, DPP-IV IC50=26 nM) exhibited good oral bioavailability and acceptable half-life in the rat, albeit with rather high clearance.
Ashton
Wallace T
WT
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. wally_ashton@merck.com
Sisco
Rosemary M
RM
Dong
Hong
H
Lyons
Kathryn A
KA
He
Huaibing
H
Doss
George A
GA
Leiting
Barbara
B
Patel
Reshma A
RA
Wu
Joseph K
JK
Marsilio
Frank
F
Thornberry
Nancy A
NA
Weber
Ann E
AE
D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D007555:Isoxazoles; D010080:Oxazoles; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles; D013844:Thiazoles
D007555:Isoxazoles; D010080:Oxazoles; D010880:Piperidines; D011480:Protease Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; D018819:Dipeptidyl Peptidase 4