Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors.
The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
Edmondson
Scott D
SD
Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. scott_edmondson@merck.com
Wei
Lan
L
Xu
Jinyou
J
Shang
Jackie
J
Xu
Shiyao
S
Pang
Jianmei
J
Chaudhary
Ashok
A
Dean
Dennis C
DC
He
Huaibing
H
Leiting
Barbara
B
Lyons
Kathryn A
KA
Patel
Reshma A
RA
Patel
Sangita B
SB
Scapin
Giovanna
G
Wu
Joseph K
JK
Beconi
Maria G
MG
Thornberry
Nancy A
NA
Weber
Ann E
AE
D000475:Alkenes / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000577:Amides / Q000737:chemistry*; D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000473:pathology; D008956:Models, Chemical; D018716:Molecular Mimicry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000475:Alkenes; D000577:Amides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006845:Hydrocarbons, Fluorinated; D007004:Hypoglycemic Agents