199296-27-0Relevant academic research and scientific papers
Novel pyrazinone inhibitors of mast cell tryptase: Synthesis and SAR evaluation
Hopkins, Corey,Neuenschwander, Kent,Scotese, Anthony,Jackson, Sharon,Nieduzak, Thaddeus,Pauls, Henry,Liang, Guyan,Sides, Keith,Cramer, Dona,Cairns, Jennifer,Maignan, Sebastien,Mathieu, Magali
, p. 4819 - 4823 (2007/10/03)
In this manuscript, the synthesis and SAR evaluation of a novel pyrazinone class of tryptase inhibitors is described. Chemical optimization of the P1 and P4 groups led to the identification of 7p (Ki = 93 nM) as a potent inhibitor of mast cell tryptase.
Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
Parlow, John J.,Case, Brenda L.,Dice, Thomas A.,Fenton, Ricky L.,Hayes, Michael J.,Jones, Darin E.,Neumann, William L.,Wood, Rhonda S.,Lachance, Rhonda M.,Girard, Thomas J.,Nicholson, Nancy S.,Clare, Michael,Stegeman, Roderick A.,Stevens, Anna M.,Stallings, William C.,Kurumbail, Ravi G.,South, Michael S.
, p. 4050 - 4062 (2007/10/03)
Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure of a tripeptide-α-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S1, S2, and S3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P1, P2, and P3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/VIIa with excellent selectivity over thrombin (IIa) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.
Non-covalent thrombin inhibitors featuring P3-heterocycles with P1-monocyclic arginine surrogates
Reiner, John E.,Siev, Daniel V.,Araldi, Gian-Luca,Cui, Jingrong Jean,Ho, Jonathan Z.,Reddy, Komandla Malla,Mamedova, Lala,Vu, Phong H.,Lee, Kuen-Shan S.,Minami, Nathaniel K.,Gibson, Tony S.,Anderson, Susanne M.,Bradbury, Annette E.,Nolan, Thomas G.,Semple, J. Edward
, p. 1203 - 1208 (2007/10/03)
Investigations on P2-P3-heterocyclic dipeptide surrogates directed towards identification of an orally bioavailable thrombin inhibitor led us to pursue novel classes of achiral, non-covalent P1-arginine derivatives. The design, synthesis, and biological activity of inhibitors NC1-NC30 that feature three classes of monocyclic P1-arginine surrogates will be disclosed: (1) (hetero)aromatic amidines, amines and hydroxyamidines, (2) 2-aminopyrazines, and (3) 2-aminopyrimidines and 2-aminotetrahydropyrimidines.
Thrombin inhibitors
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, (2008/06/13)
Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure:
Efficacious, orally bioavailable thrombin inhibitors based on 3- aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates
Sanderson, Philip E. J.,Lyle, Terry A.,Cutrona, Kellie J.,Dyer, Dona L.,Dorsey, Bruce D.,McDonough, Colleen M.,Naylor-Olsen, Adel M.,Chen, I.-Wu,Chen, Zhongguo,Cook, Jacquelynn J.,Cooper, Carolyn M.,Gardell, Stephen J.,Hare, Timothy R.,Krueger, Julie A.,Lewis, S. Dale,Lin, Jiunn H.,Lucas Jr., Bobby J.,Lyle, Elizabeth A.,Lynch Jr., Joseph J.,Stranieri, Maria T.,Vastag, Kari,Yan, Youwei,Shafer, Jules A.,Vacca, Joseph P.
, p. 4466 - 4474 (2007/10/03)
We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3- sulfonylaminopyridinone core.
