title: Design, synthesis, and activity of a novel series of factor Xa inhibitors: optimization of arylamidine groups.
abstract: A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.
authors.affiliation: Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, P.O. Box 4099, Richmond, CA 94804-0099, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
authors.forename: William J
authors.initials: WJ
authors.lastname: Guilford
authors.forename: Brad O
authors.initials: BO
authors.lastname: Buckman
authors.forename: David D
authors.initials: DD
authors.lastname: Davey
authors.forename: Keith A
authors.initials: KA
authors.lastname: Eagen
authors.forename: Sunil
authors.initials: S
authors.lastname: Koovakkat
authors.forename: Amy
authors.initials: A
authors.lastname: Liang
authors.forename: Meg
authors.initials: M
authors.lastname: McCarrick
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
authors.forename: Howard P
authors.initials: HP
authors.lastname: Ng
authors.forename: Michael
authors.initials: M
authors.lastname: Pinkerton
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Elena
authors.initials: E
authors.lastname: Ho
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Shung
authors.initials: S
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Michael M
authors.initials: MM
authors.lastname: Morrissey
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry
chemical_list: D000578:Amidines; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D014357:Trypsin; D013917:Thrombin; D015951:Factor Xa