title: Generation of potent coagulation protease inhibitors utilizing zinc-mediated chelation.
abstract: Inhibition of coagulation proteases such as thrombin, fXa, and fVIIa has been a focus of ongoing research to produce safe and effective antithrombotic agents. Herein, we describe a unique zinc-mediated chelation strategy to streamline the discovery of potent inhibitors of fIIa, fXa, and fVIIa. SAR studies that led to the development of selective inhibitors of fXa will also be detailed.
authors.affiliation: Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. Wendy.Young@Celera.com
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.forename: Paul
authors.initials: P
authors.lastname: Sprengeler
authors.forename: William D
authors.initials: WD
authors.lastname: Shrader
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
authors.forename: Erik
authors.initials: E
authors.lastname: Verner
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenkins
authors.forename: Paul
authors.initials: P
authors.lastname: Fatheree
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kolesnikov
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
authors.forename: Lynne
authors.initials: L
authors.lastname: Cregar
authors.forename: Kyle
authors.initials: K
authors.lastname: Elrod
authors.forename: Brad
authors.initials: B
authors.lastname: Katz
mesh_terms: D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D002614:Chelating Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005167:Factor VII / Q000037:antagonists & inhibitors; D065427:Factor Xa Inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D015032:Zinc / Q000737:chemistry*
chemical_list: D000925:Anticoagulants; D002614:Chelating Agents; D065427:Factor Xa Inhibitors; D011480:Protease Inhibitors; D005167:Factor VII; D013917:Thrombin; D015032:Zinc