Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF–FVIIa inhibitors

Journal Article · Tue Jan 29 23:00:00 EST 2013 · Bioorganic & Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2013.01.094· OSTI ID:1353261

Zhang, Xiaojun; Glunz, Peter W.; Jiang, Wen; Schmitt, Aaron; Newman, Makenzie; Barbera, Frank A.; Bozarth, Jeffery M.; Rendina, Alan R.; Wei, Anzhi; Wen, Xiao; Rossi, Karen A.; Luettgen, Joseph M.; Wong, Pancras C.; Knabb, Robert M.; Wexler, Ruth R.; Scott Priestley, E.

Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF–FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1353261
• Journal Information: Bioorganic & Medicinal Chemistry Letters, Journal Name: Bioorganic & Medicinal Chemistry Letters Journal Issue: 6 Vol. 23; ISSN 0960-894X
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES