Substituted piperazines as novel dipeptidyl peptidase IV inhibitors.
Incorporation of a fluorophenyl beta-amino amide moiety into piperazine screening lead 2 has resulted in the discovery of a structurally novel series of potent and selective DP-IV inhibitors. Simplification of the molecule and incorporation of multiple fluorine atoms on the phenyl ring has provided low molecular weight analogs such as compound 32, which is a 19nM DP-IV inhibitor with >4000-fold selectivity over QPP.
Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. linda_brockunier@merck.com
Linda L
LL
Brockunier
Jiafang
J
He
Lawrence F
LF
Colwell
Bahanu
B
Habulihaz
Huaibing
H
He
Barbara
B
Leiting
Kathryn A
KA
Lyons
Frank
F
Marsilio
Reshma A
RA
Patel
Yohannes
Y
Teffera
Joseph K
JK
Wu
Nancy A
NA
Thornberry
Ann E
AE
Weber
Emma R
ER
Parmee
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D006207:Half-Life; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010879:Piperazines; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4