title: Design, synthesis, and structure-activity relationships of unsubstituted piperazinone-based transition state factor Xa inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Millennium Pharmaceuticals Inc., 256 East Grand Ave., South San Francisco, CA 94080, USA.
authors.forename: Wenrong
authors.initials: W
authors.lastname: Huang
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Naughton
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Ting
authors.initials: T
authors.lastname: Su
authors.forename: Suiko
authors.initials: S
authors.lastname: Dam
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wong
authors.forename: Ann
authors.initials: A
authors.lastname: Arfsten
authors.forename: Susan
authors.initials: S
authors.lastname: Edwards
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Stanley
authors.initials: S
authors.lastname: Hollenbach
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: 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
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010879:Piperazines; D015842:Serine Proteinase Inhibitors