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Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3- yl}sulfonamides

CVU UK Medicinal Chemistry Department, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 05/2007; 50(7):1546-57. DOI: 10.1021/jm060870c
Source: PubMed

ABSTRACT Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

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    • "Therefore the development of antithrombotics is a major focus of pharmaceutical research 18 . Chan et al., (2007) have designed and synthesized a series of novel sulfonamides with different P1 groups that can inhibit Factor Xa. Highly selective and potent thrombin and FXa inhibitors with good anticoagulant properties have been identified and show promise for chronic oral administration. "
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    ABSTRACT: The presented study contributes to the fundamental understanding of molecular recognition of small molecules by a macromolecular host protein. The biophysical properties of a large set of systematically varied thrombin inhibitors were anatomized in detail. In particular the combination of structural information from X-ray crystallography with thermodynamic data from microcalorimetry allowed following the thermodynamically relevant differences resulting in the binding process. The approach of systematically varying biophysical properties of protein inhibitors in small steps permits conclusive statements on the contribution of individual functionalities to binding affinity, as the outstanding complexity of the binding thermodynamics could be reduced to the comparison of closely related inhibitors. Reorganization of solute molecules was explicitly considered in all discussions of the factors determining the widely varying binding affinity of the inhibitors to their target. Diese Arbeit trägt zum tieferen Verständnis der grundlegenden Prinzipien bei, die bei der Bindung eines kleinen Moleküls an ein makromolekulares Protein relevant sind. Um im Detail die attraktiven Kräfte zu beschreiben, die in einer „molekularen Erkennung“ beider Moleküle resultieren, wurde eine Serie von 96 systematisch variierten Thrombininhibitoren biophysikalisch charakterisiert. Insbesondere die Kombination von struktureller Information aus der Röntgenkristallographie mit mikrokalorimetrisch gewonnenen thermodynamischen Daten erlaubte es, relative Unterschiede in den Bindungseigenschaften der Inhibitoren zu deuten. Durch diese systematische und kleinschrittige Variation der Inhibitoren war es möglich, zuverlässige Rückschlüsse auf den Beitrag einzelner funktioneller Gruppen oder Atome zur Bindungsaffinität zu machen, da die außerordentliche Komplexität der affinitätsbestimmenden Parameter auf den direkten Vergleich sehr ähnlicher Enzymliganden reduziert werden konnte. Dabei wurde durchweg die Reorganisation des Lösungsmittel bei der Inhibitorbindung in die Diskussion der stark variierenden Bindungsaffinitäten mit einbezogen.
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    ABSTRACT: The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fxa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethenesulfonamide and these observed activity changes have been rationalised using structural studies. (c) 2007 Elsevier Ltd. All rights reserved.
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