title: Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.
abstract: FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.
authors.affiliation: Department of Medicinal Chemistry, Trigen Ltd., Emmanuel Kaye Building,1B Manresa Road, London SW3 6LR, UK. shouming_wang@yahoo.co.uk
authors.forename: Shouming
authors.initials: S
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Beck
authors.forename: Toby
authors.initials: T
authors.lastname: Blench
authors.forename: Andrew
authors.initials: A
authors.lastname: Burd
authors.forename: Stuart
authors.initials: S
authors.lastname: Buxton
authors.forename: Maja
authors.initials: M
authors.lastname: Malic
authors.forename: Tenagne
authors.initials: T
authors.lastname: Ayele
authors.forename: Shaheda
authors.initials: S
authors.lastname: Shaikh
authors.forename: Suresh
authors.initials: S
authors.lastname: Chahwala
authors.forename: Chaman
authors.initials: C
authors.lastname: Chander
authors.forename: Richard
authors.initials: R
authors.lastname: Holland
authors.forename: Sandrine
authors.initials: S
authors.lastname: Merette
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Blackney
authors.forename: Alexandra
authors.initials: A
authors.lastname: Watts
mesh_terms: D018360:Crystallography, X-Ray; D015949:Factor IXa / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D013876:Thiophenes; C088015:benzothiophene; D015949:Factor IXa