title: Structure based drug design: development of potent and selective factor IXa (FIXa) inhibitors.
abstract: On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.
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: Andrew
authors.initials: A
authors.lastname: Burd
authors.forename: Toby
authors.initials: T
authors.lastname: Blench
authors.forename: Frederic
authors.initials: F
authors.lastname: Marlin
authors.forename: Tenagne
authors.initials: T
authors.lastname: Ayele
authors.forename: Stuart
authors.initials: S
authors.lastname: Buxton
authors.forename: Claudio
authors.initials: C
authors.lastname: Dagostin
authors.forename: Maja
authors.initials: M
authors.lastname: Malic
authors.forename: Rina
authors.initials: R
authors.lastname: Joshi
authors.forename: John
authors.initials: J
authors.lastname: Barry
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sajad
authors.forename: Chiming
authors.initials: C
authors.lastname: Cheung
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: Christine
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Holthoff
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murray
authors.forename: Michael
authors.initials: M
authors.lastname: Blackney
authors.forename: Amanda
authors.initials: A
authors.lastname: Giddings
mesh_terms: D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D015195:Drug Design; D015949:Factor IXa / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D002219:Carbamates; D013876:Thiophenes; C088015:benzothiophene; D015949:Factor IXa