Download MendeleyDesign and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors.
Zhang, X., Glunz, P.W., Jiang, W., Schmitt, A., Newman, M., Barbera, F.A., Bozarth, J.M., Rendina, A.R., Wei, A., Wen, X., Rossi, K.A., Luettgen, J.M., Wong, P.C., Knabb, R.M., Wexler, R.R., Scott Priestley, E.(2013) Bioorg Med Chem Lett 23: 1604-1607
- PubMed: 23416003
- DOI: https://doi.org/10.1016/j.bmcl.2013.01.094
- Primary Citation of Related Structures:
4ISI - PubMed Abstract:
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.
Organizational Affiliation:
Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States. xiaojun.zhang@bms.com
