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.
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.
authors.affiliation: Aventis Pharma Deutschland GmbH, DI&A, Molecular Modeling, Building G 878, D-65926 Frankfurt am Main, Germany. hans.matter@aventis.com
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Defossa
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinelt
authors.forename: Peter-Michael
authors.initials: PM
authors.lastname: Blohm
authors.forename: Detlev
authors.initials: D
authors.lastname: Schneider
authors.forename: Andrea
authors.initials: A
authors.lastname: Müller
authors.forename: Silke
authors.initials: S
authors.lastname: Herok
authors.forename: Herman
authors.initials: H
authors.lastname: Schreuder
authors.forename: Alexander
authors.initials: A
authors.lastname: Liesum
authors.forename: Volker
authors.initials: V
authors.lastname: Brachvogel
authors.forename: Petra
authors.initials: P
authors.lastname: Lönze
authors.forename: Armin
authors.initials: A
authors.lastname: Walser
authors.forename: Fahad
authors.initials: F
authors.lastname: Al-Obeidi
authors.forename: Peter
authors.initials: P
authors.lastname: Wildgoose
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000577:Amides; D000578:Amidines; D065427:Factor Xa Inhibitors; D007211:Indoles; D015842:Serine Proteinase Inhibitors