Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.
We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.
Schweitzer
Barbara A
BA
Department of Medicinal and Combinatorial Chemistry, Pfizer Corp., 800 N. Lindbergh Blvd., St. Louis, MO 63167, USA. barbara.a.schweitzer@pfizer.com
Neumann
William L
WL
Rahman
Hayat K
HK
Kusturin
Carrie L
CL
Sample
Kirby R
KR
Poda
Gennadiy I
GI
Kurumbail
Ravi G
RG
Stevens
Anna M
AM
Stegeman
Roderick A
RA
Stallings
William C
WC
South
Michael S
MS
D001550:Benzamidines / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001550:Benzamidines; D005343:Fibrinolytic Agents; D011719:Pyrazines; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa; C032157:benzamidine