Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex.
Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P(2) surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P(1) and P(3) moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC(50) against TF/VIIa with >6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis.
South
Michael S
MS
Department of Medicinal and Combinatorial Chemistry, Pharmacia Corporation, 63167, St. Louis, MO, USA. michael.s.south@pharmacia.com
Case
Brenda L
BL
Wood
Rhonda S
RS
Jones
Darin E
DE
Hayes
Michael J
MJ
Girard
Thomas J
TJ
Lachance
Rhonda M
RM
Nicholson
Nancy S
NS
Clare
Michael
M
Stevens
Anna M
AM
Stegeman
Roderick A
RA
Stallings
William C
WC
Kurumbail
Ravi G
RG
Parlow
John J
JJ
D018360:Crystallography, X-Ray; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D019151:Peptide Library; D011516:Prothrombin / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007202:Indicators and Reagents; D019151:Peptide Library; D011719:Pyrazines; D014361:Trypsin Inhibitors; D011516:Prothrombin; C025337:Factor IIa; D015942:Factor VIIa; D013917:Thrombin