Discovery of potent and selective beta-homophenylalanine based dipeptidyl peptidase IV inhibitors.
Modification of in-house screening lead beta-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC(50)=270, 119nM, respectively).
Xu
Jinyou
J
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. jinyou_xu@merck.com
Ok
Hyun O
HO
Gonzalez
Edward J
EJ
Colwell
Lawrence F
LF
Habulihaz
Bahanu
B
He
Huaibing
H
Leiting
Barbara
B
Lyons
Kathryn A
KA
Marsilio
Frank
F
Patel
Reshma A
RA
Wu
Joseph K
JK
Thornberry
Nancy A
NA
Weber
Ann E
AE
Parmee
Emma R
ER
D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D006207:Half-Life; D008745:Methylation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000613:Aminobutyrates; D011480:Protease Inhibitors; D013844:Thiazoles; C014328:2-amino-4-phenylbutyric acid; D018819:Dipeptidyl Peptidase 4