Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors.
Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.
Zhang
Penglie
P
Department of Medicinal Chemistry, Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. penglie.zhang@mpi.com
Zuckett
Jingmei F
JF
Woolfrey
John
J
Tran
Katherine
K
Huang
Brian
B
Wong
Paul
P
Sinha
Uma
U
Park
Gary
G
Reed
Andrea
A
Malinowski
John
J
Hollenbach
Stan
S
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
D000284:Administration, Oral; D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D015195:Drug Design; D065427:Factor Xa Inhibitors; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001550:Benzamidines; D065427:Factor Xa Inhibitors; D007546:Isoquinolines; D015842:Serine Proteinase Inhibitors