4-Amino cyclohexylglycine analogues as potent dipeptidyl peptidase IV inhibitors.
Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice.
Parmee
Emma R
ER
Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. emma_parmee@merck.com
He
Jiafang
J
Mastracchio
Anthony
A
Edmondson
Scott D
SD
Colwell
Larry
L
Eiermann
George
G
Feeney
William P
WP
Habulihaz
Bahanu
B
He
Huaibing
H
Kilburn
Ruth
R
Leiting
Barbara
B
Lyons
Kathryn
K
Marsilio
Frank
F
Patel
Reshma A
RA
Petrov
Aleksandr
A
Di Salvo
Jerry
J
Wu
Joseph K
JK
Thornberry
Nancy A
NA
Weber
Ann E
AE
D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats
D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D007004:Hypoglycemic Agents; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4; D005998:Glycine