Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with improved functional activity

Zhang, Penglie; Bao, Liang; Zuckett, Jingmei F; Jia, Zhaozhong J.; Woolfrey, John; Arfsten, Ann; Edwards, Susan; Sinha, Uma; Hutchaleelaha, Athiwat; Lambing, Joseph L.; Hollenbach, Stanley J.; Scarborough, Robert M.; Zhu, Bing‐Yan

doi:10.1016/j.bmcl.2003.11.080

Cited by 23 publications

(8 citation statements)

References 16 publications

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“…205 Extensive SAR exploration led to [206][207][208]. Despite the good anti-fXa activity of 206 (fXa IC 50 5 4 nM, EC 2 Â TG 5 3.2 mM), it performed poorly in the thrombin generation assay.…”

Section: Group 5 Anthranilamides Disubstituted Benzenes and Diaminmentioning

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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Section: Group 5 Anthranilamides Disubstituted Benzenes and Diaminmentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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“…Nonetheless, methyoxyphenethyl and chlorophenethyl substitutions to the core structure maintained nanomolar enzymatic inhibitory activity and increased cell based activity against 17b-HSD3 suggesting a basis for improving the cellular activity of these compounds. The use of this core structure to inhibit other molecular targets in vivo such as factor Xa [32] and the promising structure-activity relationships for 17b-HSD3 functional cell based activity reported in this study suggest that these molecules can be modified to have more favorable drug-like properties.…”

Section: Discussionmentioning

confidence: 85%

“…By screening a compound collection of $200,000 small molecules, we discovered a novel series of anthranilamide based inhibitors of 17b-HSD3 with potent activity. This core structure has also been reported as an inhibitor of factor Xa and an antagonist of M2 muscarinic receptors [32,33]. Compared to steroidal-based inhibitors of 17b-HSD3, the anthranilamides displayed a dramatic increase in enzymatic potency including a compound with low nanomolar inhibitory activity.…”

Section: Discussionmentioning

confidence: 93%

Identification of novel functional inhibitors of 17β-hydroxysteroid dehydrogenase type III (17β-HSD3)

et al. 2005

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“…Two amidine compounds, N -(3′-amidino-, and N -(4′-amidinophenyl)-3-(thiophen-2′′-ylcarbonylamino)benzamide exhibited weak thrombin, FXa, and U46619 inhibitory activities [22]. Anthranilamide derivatives have been studied as FXa inhibitors [23,24,25,26], therefore anthranilic acid was considered as central ring of diamide to improve the activity. We now report the synthesis and evaluation of the thrombin, FXa, and U46619 inhibitory activities of non-amidino N 2 -thiophenecarbonyl- and N 2 -tosylanthranilamides and amidino N 2 -thiophenecarbonyl- and N 2 -tosylanthranilamides.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides

Lee

Nguyen

et al. 2017

IJMS

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Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N2-thiophencarbonyl- and N2-tosyl anthranilamides 1–20 and six amidino N2-thiophencarbonyl- and N2-tosylanthranilamides 21–26 were synthesized to evaluate their activated partial thromboplastin time (aPTT) and prothrombin time (PT) using human plasma at a concentration of 30 µg/mL in vitro. As a result, compounds 5, 9, and 21–23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21–23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21–23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced by U46619 in vitro and ex vivo. Among the derivatives evaluated, N-(3′-amidinophenyl)-2-((thiophen-2′′-yl)carbonylamino)benzamide (21) was the most active compound.

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Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with improved functional activity

Cited by 23 publications

References 16 publications

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Identification of novel functional inhibitors of 17β-hydroxysteroid dehydrogenase type III (17β-HSD3)

Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides

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