Thiophene-Anthranilamides as Highly Potent and Orally Available Factor Xa Inhibitors

Ye, Bin; Arnaiz, Damian O.; Chou, Yuo-Ling; Griedel, Brian D.; Karanjawala, Rushad; Lee, Wheeseong; Morrissey, Michael M.; Sacchi, Karna L.; Sakata, S. T.; Shaw, Kenneth J.; Wu, Shung C.; Zhao, Ziyu; Adler, Marc; Cheeseman, Sarah H.; Dole, William P.; Ewing, Janice; Fitch, Richard W.; Lentz, Dao; Liang, Amy; Light, David R.; Morser, John; Post, Joseph; Rumennik, Galina; Subramanyam, Babu; Sullivan, M.; Vergona, Ronald; Walters, Janette; Wang, Yixin; White, Kathy; Whitlow, Marc; Kochanny, Monica J.

doi:10.1021/jm070125f

Cited by 43 publications

(25 citation statements)

References 30 publications

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“…There are strong electronic influences and π–π stacking effects that can shift ligand affinities over 4 orders of magnitude. Structure 2p3t(67) (set 1, complex no. 141) is a good example of the difficulty in modeling some high-affinity inhibitors of FXa.…”

Section: Resultsmentioning

confidence: 99%

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

Smith

Dunbar

Ung

et al. 2011

J. Chem. Inf. Model.

141

178

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As part of the Community Structure-Activity Resource (CSAR) center, a set of 343 high-quality, protein–ligand crystal structures were assembled with experimentally determined Kd or Ki information from the literature. We encouraged the community to score the crystallographic poses of the complexes by any method of their choice. The goal of the exercise was to (1) evaluate the current ability of the field to predict activity from structure and (2) investigate the properties of the complexes and methods that appear to hinder scoring. A total of 19 different methods were submitted with numerous parameter variations for a total of 64 sets of scores from 16 participating groups. Linear regression and nonparametric tests were used to correlate scores to the experimental values. Correlation to experiment for the various methods ranged R2 = 0.58–0.12, Spearman ρ = 0.74–0.37, Kendall τ = 0.55–0.25, and median unsigned error = 1.00–1.68 pKd units. All types of scoring functions—force field based, knowledge based, and empirical—had examples with high and low correlation, showing no bias/advantage for any particular approach. The data across all the participants were combined to identify 63 complexes that were poorly scored across the majority of the scoring methods and 123 complexes that were scored well across the majority. The two sets were compared using a Wilcoxon rank-sum test to assess any significant difference in the distributions of >400 physicochemical properties of the ligands and the proteins. Poorly scored complexes were found to have ligands that were the same size as those in well-scored complexes, but hydrogen bonding and torsional strain were significantly different. These comparisons point to a need for CSAR to develop data sets of congeneric series with a range of hydrogen-bonding and hydrophobic characteristics and a range of rotatable bonds.

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Section: Resultsmentioning

confidence: 99%

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

Smith

Dunbar

Ung

et al. 2011

J. Chem. Inf. Model.

141

178

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“…213 Installation of a methoxy group at C-3 and replacement of chloroaniline with a chloroaminopyridine at P1 in 216 increased potency by about fivefold to a K i of 0.16 nM in 217 and improved activity in the PT assay. An extensive SAR study was performed on the P4 of 217, which resulted in 218-220.…”

Section: Factor Xa Inhibitors For Thromboembolic Disorders K 247mentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.

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“…A 10-30-fold improvement in prothrombin time was achieved with ZK 813039 (63) and ZK 810388 (64), respectively, by using a chloropyridine instead of a chloroaniline P1 group [36]. This resulted in an additional water-mediated hydrogen bond from the pyridine nitrogen to the active site Ser195 and generally increased binding affinity 2-15-fold [37].…”

Section: Synopsis On Non-basic P1 Groupsmentioning

confidence: 99%

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

Straub¹,

Roehrig²,

Hillisch³

2010

CTMC

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Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed.

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Thiophene-Anthranilamides as Highly Potent and Orally Available Factor Xa Inhibitors

Cited by 43 publications

References 30 publications

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

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Thiophene-Anthranilamides as Highly Potent and Orally Available Factor Xa Inhibitors

Cited by 43 publications

References 30 publications

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto&#8482; (Rivaroxaban)

Contact Info

Product

Resources

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Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)