Design and Quantitative Structure−Activity Relationship of 3-Amidinobenzyl-1H-indole-2-carboxamides as Potent, Nonchiral, and Selective Inhibitors of Blood Coagulation Factor Xa

A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure−activity relationship (QSAR) studies (CoMFA, CoMSIA) i...

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Veröffentlicht in:Journal of medicinal chemistry 2002-06, Vol.45 (13), p.2749-2769
Hauptverfasser: Matter, Hans, Defossa, Elisabeth, Heinelt, Uwe, Blohm, Peter-Michael, Schneider, Detlev, Müller, Andrea, Herok, Silke, Schreuder, Herman, Liesum, Alexander, Brachvogel, Volker, Lönze, Petra, Walser, Armin, Al-Obeidi, Fahad, Wildgoose, Peter
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container_end_page 2769
container_issue 13
container_start_page 2749
container_title Journal of medicinal chemistry
container_volume 45
creator Matter, Hans
Defossa, Elisabeth
Heinelt, Uwe
Blohm, Peter-Michael
Schneider, Detlev
Müller, Andrea
Herok, Silke
Schreuder, Herman
Liesum, Alexander
Brachvogel, Volker
Lönze, Petra
Walser, Armin
Al-Obeidi, Fahad
Wildgoose, Peter
description A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure−activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein−ligand interactions responsible for biological affinity and selectivity. Several compounds from this series are highly potent and selective inhibitors of this important enzyme linking extrinsic and intrinsic coagulation pathways. To rationalize biological affinity and to provide guidelines for further design, all compounds were docked into the factor Xa binding site. Those docking studies were based on X-ray structures of factor Xa in complex with literature-known inhibitors. It was possible to validate those binding modes by four X-ray crystal structures of representative ligands in factor Xa, while one ligand was additionally crystallized in trypsin to rationalize requirements for selective factor Xa inhibition. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r 2 values using the leave-one-out method and repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined factor Xa binding site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. The final quantitative SAR information agrees with all experimental data for the binding topology and thus provides reasonable activity predictions for novel factor Xa inhibitors.
doi_str_mv 10.1021/jm0111346
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Med. Chem</addtitle><description>A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure−activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein−ligand interactions responsible for biological affinity and selectivity. Several compounds from this series are highly potent and selective inhibitors of this important enzyme linking extrinsic and intrinsic coagulation pathways. To rationalize biological affinity and to provide guidelines for further design, all compounds were docked into the factor Xa binding site. Those docking studies were based on X-ray structures of factor Xa in complex with literature-known inhibitors. 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Med. Chem</addtitle><date>2002-06-20</date><risdate>2002</risdate><volume>45</volume><issue>13</issue><spage>2749</spage><epage>2769</epage><pages>2749-2769</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure−activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein−ligand interactions responsible for biological affinity and selectivity. Several compounds from this series are highly potent and selective inhibitors of this important enzyme linking extrinsic and intrinsic coagulation pathways. To rationalize biological affinity and to provide guidelines for further design, all compounds were docked into the factor Xa binding site. Those docking studies were based on X-ray structures of factor Xa in complex with literature-known inhibitors. It was possible to validate those binding modes by four X-ray crystal structures of representative ligands in factor Xa, while one ligand was additionally crystallized in trypsin to rationalize requirements for selective factor Xa inhibition. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r 2 values using the leave-one-out method and repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined factor Xa binding site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. The final quantitative SAR information agrees with all experimental data for the binding topology and thus provides reasonable activity predictions for novel factor Xa inhibitors.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>12061878</pmid><doi>10.1021/jm0111346</doi><tpages>21</tpages></addata></record>
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subjects Amides - chemical synthesis
Amides - chemistry
Amidines - chemical synthesis
Amidines - chemistry
Binding Sites
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Crystallography, X-Ray
Drug Design
Factor Xa Inhibitors
Indoles - chemical synthesis
Indoles - chemistry
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Protein Binding
Quantitative Structure-Activity Relationship
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - chemistry
Stereoisomerism
title Design and Quantitative Structure−Activity Relationship of 3-Amidinobenzyl-1H-indole-2-carboxamides as Potent, Nonchiral, and Selective Inhibitors of Blood Coagulation Factor Xa
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