Design, synthesis, and structure-activity relationships of unsubstituted piperazinone-based transition state factor Xa inhibitors.
A series of novel transition state factor Xa inhibitors containing a variety of lactam ring systems as central templates was synthesized in an expedient manner and allowed for a great deal of structural variability. Among them, the piperazinone-based inhibitors were found to be not only active against factor Xa but also selective over thrombin. Optimization of the P4 moiety yielded several potent compounds with IC(50) below 1 nM against factor Xa.
Huang
Wenrong
W
Department of Medicinal Chemistry, Millennium Pharmaceuticals Inc., 256 East Grand Ave., South San Francisco, CA 94080, USA.
Naughton
Mary Ann
MA
Yang
Hua
H
Su
Ting
T
Dam
Suiko
S
Wong
Paul W
PW
Arfsten
Ann
A
Edwards
Susan
S
Sinha
Uma
U
Hollenbach
Stanley
S
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001780:Blood Coagulation Tests; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D065427:Factor Xa Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000517:prevention & control
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010879:Piperazines; D015842:Serine Proteinase Inhibitors