title: In vitro evaluation and crystallographic analysis of a new class of selective, non-amide-based thrombin inhibitors.
abstract: We describe the in vitro evaluation and crystallographic analysis of a new class of potent and selective, non-amino acid-based, small-molecule thrombin inhibitors, exemplified by 14. This class of achiral inhibitors lacks an amide-based backbone, exhibits nM inhibition of thrombin, and is selective for thrombin. Compound 14 does not interact with the active-site catalytic apparatus and is anchored to the enzyme via a single network of hydrogen bonds to Asp189 of the S1 pocket.
authors.affiliation: 3-Dimensional Pharmaceuticals, Exton, PA 19341, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lu
authors.forename: B
authors.initials: B
authors.lastname: Tomczuk
authors.forename: C R
authors.initials: CR
authors.lastname: Illig
authors.forename: R
authors.initials: R
authors.lastname: Bone
authors.forename: L
authors.initials: L
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Spurlino
authors.forename: F R
authors.initials: FR
authors.lastname: Salemme
authors.forename: R M
authors.initials: RM
authors.lastname: Soll
mesh_terms: D000577:Amides / Q000737:chemistry; D000991:Antithrombins / Q000737:chemistry / Q000494:pharmacology*; D003461:Crystallography; D004341:Drug Evaluation; D006860:Hydrogen Bonding; D015394:Molecular Structure
chemical_list: D000577:Amides; D000991:Antithrombins