title: N(2)-Aroylanthranilamide inhibitors of human factor Xa.
abstract: Reversal of the A-ring amide link in 1,2-dibenzamidobenzene 1 (fXa K(ass) = 0.81 x 10(6) L/mol) led to a series of human factor Xa (hfXa) inhibitors based on N(2)-aroylanthranilamide 4. Expansion of the SAR around 4 showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of hfXa. Bulky groups such as 4-isopropyl, 4-tert-butyl, and 4-dimethylamino were favored in the B-ring to interact with the S4 site of hfXa. The central (C) ring containing a 5-methanesulfonamido group yielded greater activity than carbamoyl groups. Combining the beneficial features from the B- and C-ring SAR, compound 55 represents the most potent hfXa inhibitor in the N(2)-aroylanthranilamide 4 series with hfXa K(ass) = 58 x 10(6) L/mol (K(i) = 11.5 nM).
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
authors.forename: Y K
authors.initials: YK
authors.lastname: Yee
authors.forename: A L
authors.initials: AL
authors.lastname: Tebbe
authors.forename: J H
authors.initials: JH
authors.lastname: Linebarger
authors.forename: D W
authors.initials: DW
authors.lastname: Beight
authors.forename: T J
authors.initials: TJ
authors.lastname: Craft
authors.forename: D
authors.initials: D
authors.lastname: Gifford-Moore
authors.forename: T
authors.initials: T
authors.lastname: Goodson
authors.forename: D K
authors.initials: DK
authors.lastname: Herron
authors.forename: V J
authors.initials: VJ
authors.lastname: Klimkowski
authors.forename: J A
authors.initials: JA
authors.lastname: Kyle
authors.forename: J S
authors.initials: JS
authors.lastname: Sawyer
authors.forename: G F
authors.initials: GF
authors.lastname: Smith
authors.forename: J M
authors.initials: JM
authors.lastname: Tinsley
authors.forename: R D
authors.initials: RD
authors.lastname: Towner
authors.forename: L
authors.initials: L
authors.lastname: Weir
authors.forename: M R
authors.initials: MR
authors.lastname: Wiley
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: C406227:2-(4-(dimethylamino)benzoylamino)-5-methanesulfonylamino-N'-(4-methoxyphenyl)benzamide; D000925:Anticoagulants; D001549:Benzamides; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D013449:Sulfonamides; D015951:Factor Xa