Selective and dual action orally active inhibitors of thrombin and factor Xa

Young, Robert J.; Brown, David F.M.; Burns-Kurtis, Cynthia L.; Chan, Carmel T.; Convery, M.A.; Hubbard, Julia A.; Kelly, Henry A.; Pateman, Anthony J.; Patikis, Angela; Senger, Stefan; Shah, Gita P.; Toomey, John R.; Watson, Nigel S.; Zhou, Ping

doi:10.1016/j.bmcl.2007.03.080

Cited by 22 publications

(21 citation statements)

References 16 publications

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“…The experimental data show that addition of a 1-methyl group to the vinylsulfonamide linker lowers the K i from 367 nM to 2 nM. 23 The MC/FEP calculations for the conversion of 16 to 17 gave a consistent result favoring the binding of 17 by 3.7 ± 0.3 kcal/mol.…”

Section: Resultsmentioning

confidence: 91%

“…The image is more of the methyl group being inserted along the hydrophobic surface formed by the C α and C β of Glu192. Using the default hydration procedure in MCPRO , water molecules are found proximal to four of the seven crystallographic hydration sites near the ligand, 23 as shown in Figure 8. Most notably, the two relatively isolated water sites between Glu192 and the morpholine ring of 17 are not occupied in the MC simulations.…”

Section: Resultsmentioning

confidence: 99%

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Methyl Effects on Protein–Ligand Binding

et al. 2012

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The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of ten or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/Free Energy Perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38α MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Methyl Effects on Protein–Ligand Binding

et al. 2012

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“…Thermanox cover slips were from Nunc (USA). 813893 (also known as GW813893, 2-(5-chlorothien-2-yl)-N-(1-(1-methyl-2-(morpholin-4-yl)-2-oxoethyl)-2-oxopyrrolidin-3-yl)ethenesulfonamide, C 17 H 22 ClN 3 O 5 S 2 , MW: 447.5, [20][21][22]) and Razaxaban (1-(3 0 -Aminobenzisoxazol-5 0 -yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2 0 -dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride, MW: 564.9, [19,23]) were synthesised at GlaxoSmithKline, Stevenage (UK). Sterile phosphate buffered saline (PBS) was from Invitrogen (UK), other reagents were from Sigma (UK) or BDH (UK).…”

Section: Methodsmentioning

confidence: 99%

The impact of factor Xa inhibition on axial dependent arterial thrombus formation triggered by a tissue factor rich surface

Pugh

Jarvis

Koch

et al. 2011

J Thromb Thrombolysis

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This study was designed to assess the effect of Factor Xa antagonists on thrombus formation at various axial positions on a tissue factor rich surface under arterial blood flow conditions. Non-anticoagulated, flowing human blood, drawn directly from an antecubital vein, was perfused over a tissue factor coated cover slip in a parallel-plate perfusion chamber. Thrombus surface coverage, thrombus mean height and fibrin surface coverage were measured at six different axial positions by confocal microscopy. Both thrombus surface coverage and mean height decreased along the cover slip axis whereas the fibrin surface coverage increased. Pre-chamber treatment of blood with the direct Factor Xa inhibitors Razaxaban and 813893 resulted in significantly reduced thrombus and fibrin formation at all axial positions investigated (P < 0.05). Thrombus and fibrin deposition in a laminar flow chamber changed with axial position with surface coverage measurements being more reproducible than thrombus mean height. Data were more reproducible towards the centre of the flow chamber than at the extremities. Razaxaban and 813893 inhibited thrombus and fibrin formation at the highest concentrations tested. No difference in drug effect was apparent at different axial positions. In conclusion, axial position influences the degree of thrombus and fibrin deposition with measurements being less reproducible at the extremities of the flow chamber. This technique may prove useful for analysing anti-thrombotic drug effects before progression to clinical trials.

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“…[72] Alle drei Verbindungen binden auf ähnliche Weise an Thrombin: Die Chlorthienylgruppe fungiert als S1-Binder, die Carbonylgruppe des Pyrrolidins wechselwirkt mit dem Proteinrückgrat, und der Morpholin- [73,74] es liegen jedoch keine Informationen über eine weitere Entwicklung dieser Verbindungsklasse vor.…”

Section: Duale Thrombin/faktor-xa-inhibitorenunclassified

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

2011

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Bislang müssen sich Patienten zur Vorbeugung von Thrombosen nach Operationen täglich Heparin spritzen oder müssen zur Schlaganfallprophylaxe bei Vorhofflimmern Vitamin‐K‐Antagonisten vom Cumarintyp einnehmen, die eine geringe therapeutische Breite haben und deren Dosierung regelmäßig überwacht werden muss. Um den Therapiestandard bei thromboembolischen Erkrankungen, wie tiefen Venenthrombosen, Lungenembolien und Hirnschlag bei Vorhofflimmern, zu verbessern, wurde in der letzten Dekade intensiv an neuen, oral wirksamen Thrombin‐ und Faktor‐Xa‐Inhibitoren geforscht. Einige dieser Verbindungen sind bereits auf dem Markt oder befinden sich in fortgeschrittener klinischer Entwicklung; sie könnten den Antikoagulantienmarkt revolutionieren.

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Selective and dual action orally active inhibitors of thrombin and factor Xa

Cited by 22 publications

References 16 publications

Methyl Effects on Protein–Ligand Binding

Methyl Effects on Protein–Ligand Binding

The impact of factor Xa inhibition on axial dependent arterial thrombus formation triggered by a tissue factor rich surface

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

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