title: Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy.
abstract: Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.
authors: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors: M
authors: M
authors: Zhang
authors: D L
authors: DL
authors: Bailey
authors: J A
authors: JA
authors: Bastian
authors: S L
authors: SL
authors: Briggs
authors: N Y
authors: NY
authors: Chirgadze
authors: D K
authors: DK
authors: Clawson
authors: M L
authors: ML
authors: Denney
authors: D S
authors: DS
authors: Gifford-Moore
authors: R W
authors: RW
authors: Harper
authors: L M
authors: LM
authors: Johnson
authors: V J
authors: VJ
authors: Klimkowski
authors: T J
authors: TJ
authors: Kohn
authors: H S
authors: HS
authors: Lin
authors: J R
authors: JR
authors: McCowan
authors: M E
authors: ME
authors: Richett
authors: D J
authors: DJ
authors: Sall
authors: A J
authors: AJ
authors: Smith
authors: G F
authors: GF
authors: Smith
authors: D W
authors: DW
authors: Snyder
authors: K
authors: K
authors: Takeuchi
authors: B G
authors: BG
authors: Utterback
authors: S C
authors: SC
authors: Yan
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D013876:Thiophenes; C088015:benzothiophene; D013917:Thrombin