Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors.
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.
T10 T11 T12 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-Y
FVIIa TF FVIIa Bicyclic pyrazinone and pyrimidinone amides hydrogen bicyclic pyrazinone and pyrimidinone amides FVIIa FVIIa FVIIa FIXa, Xa, XIa chymotrypsin TF