Structure based drug design: development of potent and selective factor IXa (FIXa) inhibitors.
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.
Wang
Shouming
S
Department of Medicinal Chemistry, Trigen Ltd., Emmanuel Kaye Building, 1B Manresa Road,London SW3 6LR, UK. shouming_wang@yahoo.co.uk
Beck
Richard
R
Burd
Andrew
A
Blench
Toby
T
Marlin
Frederic
F
Ayele
Tenagne
T
Buxton
Stuart
S
Dagostin
Claudio
C
Malic
Maja
M
Joshi
Rina
R
Barry
John
J
Sajad
Mohammed
M
Cheung
Chiming
C
Shaikh
Shaheda
S
Chahwala
Suresh
S
Chander
Chaman
C
Baumgartner
Christine
C
Holthoff
Hans-Peter
HP
Murray
Elizabeth
E
Blackney
Michael
M
Giddings
Amanda
A
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
D002219:Carbamates; D013876:Thiophenes; C088015:benzothiophene; D015949:Factor IXa