Cation-pi interactions at the active site of factor Xa: dramatic enhancement upon stepwise N-alkylation of ammonium ions.

A new class of potent inhibitors of factor Xa features a quaternary ammonium ion to fill the aromatic box in the S4 pocket and a 2-chlorothiophenyl group to occupy the S1 pocket (see picture; red O, blue N, yellow S, green Cl). Changing from a primary to a quaternary ammonium ion increases the binding affinity by a factor of 1000. The poor affinity in the former case suggests negligible cation- interactions between Lys and Trp.

[1]  S. Haas.  New oral Xa and IIa inhibitors: updates on clinical trial results , 2008, Journal of Thrombosis and Thrombolysis.

[2]  W. B. Schweizer,et al.  Molekulare Torsionswaagen: Anzeichen für attraktive orthogonale dipolare Wechselwirkungen zwischen organischem Fluor und Amidgruppen† , 2007 .

[3]  F. Diederich,et al.  Molecular torsion balances: evidence for favorable orthogonal dipolar interactions between organic fluorine and amide groups. , 2007, Angewandte Chemie.

[4]  Angela Smallwood,et al.  Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. , 2007, Journal of medicinal chemistry.

[5]  M. Waters,et al.  Effects of Chain Length and N‐Methylation on a Cation–π Interaction in a β‐Hairpin Peptide , 2007 .

[6]  S. Tsuzuki,et al.  Origin of attraction, magnitude, and directionality of interactions in benzene complexes with pyridinium cations. , 2007, Journal of the American Chemical Society.

[7]  A. Turpie.  Oral, Direct Factor Xa Inhibitors in Development for the Prevention and Treatment of Thromboembolic Diseases , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[8]  Margaret M. Elvekrog,et al.  Environmental modulation of protein cation-pi interactions. , 2007, Journal of the American Chemical Society.

[9]  Manfred Kansy,et al.  A Fluorine Scan at the Catalytic Center of Thrombin: CF, COH, and COMe Bioisosterism and Fluorine Effects on pKa and log D Values , 2006, ChemMedChem.

[10]  G. Marshall,et al.  Relative Strength of Cation-π vs Salt-Bridge Interactions: The Gtα(340−350) Peptide/Rhodopsin System , 2006 .

[11]  Thomas Lampe,et al.  Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. , 2005, Journal of medicinal chemistry.

[12]  D. Banner,et al.  Quantifizierung von Kation‐π‐Wechselwirkungen in Protein‐Ligand‐Komplexen: Kristallstrukturanalyse eines Komplexes von Faktor Xa und einem quartären Ammonium‐Ion‐Liganden , 2005 .

[13]  François Diederich,et al.  Quantification of cation-pi interactions in protein-ligand complexes: crystal-structure analysis of Factor Xa bound to a quaternary ammonium ion ligand. , 2005, Angewandte Chemie.

[14]  Hans Matter,et al.  Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography. , 2005, Journal of medicinal chemistry.

[15]  M. Waters,et al.  Influence of N-methylation on a cation-π interaction produces a remarkably stable β-hairpin peptide , 2005 .

[16]  F. Diederich,et al.  Orthogonale multipolare Wechselwirkungen in chemischen und biologischen Strukturen , 2005 .

[17]  François Diederich,et al.  Orthogonal multipolar interactions in structural chemistry and biology. , 2005, Angewandte Chemie.

[18]  F. Kuo,et al.  Synthesis of a carbon‐14 labeled 1‐(indole‐6‐carbonyl‐D‐phenylglycinyl)‐4‐(1‐methylpiperidin‐4‐YL)piperazine‐[carbonyl‐14C], LY517717‐[14C], a factor Xa inhibitor , 2004 .

[19]  François Diederich,et al.  Wechselwirkungen mit aromatischen Ringen in chemischen und biologischen Erkennungsprozessen , 2003 .

[20]  F. Diederich,et al.  Interactions with aromatic rings in chemical and biological recognition. , 2003, Angewandte Chemie.

[21]  Gerhard Klebe,et al.  Utilising structural knowledge in drug design strategies: applications using Relibase. , 2003, Journal of molecular biology.

[22]  Gerhard Klebe,et al.  Relibase: design and development of a database for comprehensive analysis of protein-ligand interactions. , 2003, Journal of molecular biology.

[23]  Robert Leadley,et al.  Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand. , 2003, Journal of medicinal chemistry.

[24]  Sébastien Maignan,et al.  Molecular structures of human factor Xa complexed with ketopiperazine inhibitors: preference for a neutral group in the S1 pocket. , 2003, Journal of medicinal chemistry.

[25]  Bin Ye,et al.  Crystal structures of two potent nonamidine inhibitors bound to factor Xa. , 2002, Biochemistry.

[26]  Daniel L Cheney,et al.  Optimization of the beta-aminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent In vivo anticoagulant activity. , 2002, Bioorganic & medicinal chemistry letters.

[27]  Dennis A Dougherty,et al.  Cation-pi interactions in ligand recognition and catalysis. , 2002, Trends in pharmacological sciences.

[28]  F. Diederich,et al.  Synthesis of Novel Nonpeptidic Thrombin Inhibitors , 2000 .

[29]  D. A. Dougherty,et al.  Cation-π interactions in structural biology , 1999 .

[30]  D. A. Dougherty,et al.  The Cationminus signpi Interaction. , 1997, Chemical reviews.

[31]  D. A. Dougherty,et al.  Cation-π Interactions in Chemistry and Biology: A New View of Benzene, Phe, Tyr, and Trp , 1996, Science.

[32]  Paul R. Gerber,et al.  MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry , 1995, J. Comput. Aided Mol. Des..

[33]  D A Dougherty,et al.  Acetylcholine binding by a synthetic receptor: implications for biological recognition , 1990, Science.