Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex.
Multistep syntheses of substituted benzenes and benzoquinone inhibitors of tissue Factor VIIa are reported. The benzene analogues were designed such that their substitution pattern would occupy and interact with the S(1), S(2), and S(3) pockets of the tissue Factor VIIa (TF/VIIa) enzyme. The compounds exhibited modest potency on TF/VIIa with selectivity over Factor Xa and thrombin. The X-ray crystal structures of the targeted fluorobenzene 12a and benzoquinone 14 inhibitors bound to TF/VIIa were obtained and will be described.
Parlow
John J
JJ
Department of Medicinal and Combinatorial Chemistry, Pharmacia Corporation, 800 North Lindbergh Boulevard, St. Louis, MO 63167, USA. john.j.parlow@pfizer.com
Kurumbail
Ravi G
RG
Stegeman
Roderick A
RA
Stevens
Anna M
AM
Stallings
William C
WC
South
Michael S
MS
D016227:Benzoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D005464:Fluorobenzenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D007659:Ketones; D008958:Models, Molecular; D013379:Substrate Specificity
D016227:Benzoquinones; D005464:Fluorobenzenes; D007202:Indicators and Reagents; D007659:Ketones; D015942:Factor VIIa