title: Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors.
abstract: Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.
authors.affiliation: DuPont Pharmaceuticals Company, Wilmington, DE 19880-0500, USA.
authors.forename: C
authors.initials: C
authors.lastname: Dominguez
authors.forename: D E
authors.initials: DE
authors.lastname: Duffy
authors.forename: Q
authors.initials: Q
authors.lastname: Han
authors.forename: R S
authors.initials: RS
authors.lastname: Alexander
authors.forename: R A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: J M
authors.initials: JM
authors.lastname: Park
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: E C
authors.initials: EC
authors.lastname: Amparo
authors.forename: R M
authors.initials: RM
authors.lastname: Knabb
authors.forename: J
authors.initials: J
authors.lastname: Luettgen
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats
chemical_list: D000578:Amidines; D000991:Antithrombins; D006571:Heterocyclic Compounds; D007211:Indoles; C119484:XU 817