Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors incorporating substituted biphenyl P4 motifs.
Anthranilamides 4 and 5 were designed and synthesized as selective and orally bioavailable factor Xa inhibitors. Structural modifications aimed at lowering their lipophilicity were performed at the central phenyl ring and at the S4 binding biphenyl region by incorporating water solublizing substituents. The resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro, and show improved activity in human plasma-based thrombin generation assay.
Zhang
Penglie
P
Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. penglie.zhang@mpi.com
Bao
Liang
L
Zuckett
Jingmei F
JF
Goldman
Erick A
EA
Jia
Zhaozhong J
ZJ
Arfsten
Ann
A
Edwards
Susan
S
Sinha
Uma
U
Hutchaleelaha
Athiwat
A
Park
Gary
G
Lambing
Joseph L
JL
Hollenbach
Stanley J
SJ
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D065427:Factor Xa Inhibitors; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology*
D000577:Amides; D065427:Factor Xa Inhibitors; D062367:ortho-Aminobenzoates