title: Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors.
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.
authors: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States. xiaojun.zhang@bms.com
authors: Xiaojun
authors: X
authors: Zhang
authors: Peter W
authors: PW
authors: Glunz
authors: Wen
authors: W
authors: Jiang
authors: Aaron
authors: A
authors: Schmitt
authors: Makenzie
authors: M
authors: Newman
authors: Frank A
authors: FA
authors: Barbera
authors: Jeffery M
authors: JM
authors: Bozarth
authors: Alan R
authors: AR
authors: Rendina
authors: Anzhi
authors: A
authors: Wei
authors: Xiao
authors: X
authors: Wen
authors: Karen A
authors: KA
authors: Rossi
authors: Joseph M
authors: JM
authors: Luettgen
authors: Pancras C
authors: PC
authors: Wong
authors: Robert M
authors: RM
authors: Knabb
authors: Ruth R
authors: RR
authors: Wexler
authors: E
authors: E
authors: Scott Priestley
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000578:Amidines; D001643:Bridged Bicyclo Compounds; D011719:Pyrazines; D011744:Pyrimidinones; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa