title: Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex.
abstract: 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.
authors.affiliation: Department of Medicinal and Combinatorial Chemistry, Pharmacia Corporation, 63167, St. Louis, MO, USA. michael.s.south@pharmacia.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: South
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Case
authors.forename: Rhonda S
authors.initials: RS
authors.lastname: Wood
authors.forename: Darin E
authors.initials: DE
authors.lastname: Jones
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hayes
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Girard
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Lachance
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Nicholson
authors.forename: Michael
authors.initials: M
authors.lastname: Clare
authors.forename: Anna M
authors.initials: AM
authors.lastname: Stevens
authors.forename: Roderick A
authors.initials: RA
authors.lastname: Stegeman
authors.forename: William C
authors.initials: WC
authors.lastname: Stallings
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.forename: John J
authors.initials: JJ
authors.lastname: Parlow
mesh_terms: 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
chemical_list: 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