602280-43-3Relevant academic research and scientific papers
Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket
Gising, Johan,Belfrage, Anna Karin,Alogheli, Hiba,Ehrenberg, Angelica,?kerblom, Eva,Svensson, Richard,Artursson, Per,Karlén, Anders,Danielson, U. Helena,Larhed, Mats,Sandstr?m, Anja
supporting information, p. 1790 - 1801 (2014/04/03)
Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
Discovery of achiral inhibitors of the hepatitis C virus NS3 protease based on 2(1H)-pyrazinones
?rtqvist, Pernilla,Gising, Johan,Ehrenberg, Angelica E.,Vema, Aparna,Borg, Anneli,Karlén, Anders,Larhed, Mats,Danielson, U. Helena,Sandstr?m, Anja
scheme or table, p. 6512 - 6525 (2010/10/02)
Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.
A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
Gising, Johan,Oertqvist, Pernilla,Sandstroem, Anja,Larhed, Mats
supporting information; experimental part, p. 2809 - 2815 (2009/09/07)
A rapid and versatile one-pot, 2 × 10 min microwave protocol for the preparation of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The α-amino
Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
South, Michael S.,Case, Brenda L.,Wood, Rhonda S.,Jones, Darin E.,Hayes, Michael J.,Girard, Thomas J.,Lachance, Rhonda M.,Nicholson, Nancy S.,Clare, Michael,Stevens, Anna M.,Stegeman, Roderick A.,Stallings, William C.,Kurumbail, Ravi G.,Parlow, John J.
, p. 2319 - 2325 (2007/10/03)
Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P1 and P3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with >6250× selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis.
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.
