title: Exploratory solid-phase synthesis of factor Xa inhibitors: discovery and application of p3-heterocyclic amides as novel types of non-basic arginine surrogates.
abstract: A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. These neutral amide derivatives serve as novel P3 d-arginine mimics. Pyrazine carboxamide scaffolds afforded the most potent FXa inhibitors (e.g., 2b IC50 = 4.6 nM). The synthesis and biological activity of two focused libraries are reported.
authors.affiliation: Department of Medicinal Chemistry, Corvas International, Inc. San Diego, California 92121, USA.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Ho
authors.forename: O E
authors.initials: OE
authors.lastname: Levy
authors.forename: T S
authors.initials: TS
authors.lastname: Gibson
authors.forename: K
authors.initials: K
authors.lastname: Nguyen
authors.forename: J E
authors.initials: JE
authors.lastname: Semple
mesh_terms: D000577:Amides / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D006571:Heterocyclic Compounds / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D065427:Factor Xa Inhibitors; D006571:Heterocyclic Compounds; D015842:Serine Proteinase Inhibitors; D001120:Arginine