Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa

Kochanny, Monica J.; Adler, Marc; Ewing, Janice; Griedel, Brian D.; Ho, Elena; Karanjawala, Rushad; Lee, Wheeseong; Lentz, Dao; Liang, Amy; Morrissey, Michael M.; Phillips, Gary B.; Post, Joseph; Sacchi, Karna L.; Sakata, S. T.; Subramanyam, Babu; Vergona, Ronald; Walters, Janette; White, Kathy; Whitlow, Marc; Ye, Bin; Zhao, Ziyu; Shaw, Kenneth J.

doi:10.1016/j.bmc.2006.12.019

Cited by 25 publications

(26 citation statements)

References 47 publications

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“…This led to a series of thiophenes, as exemplified by 216 (fXa K i 5 1.0 nM, EC 2 Â PT 5 12 mM). 212 Compound 216 and some of its analogues also showed improved in vitro anticoagulant activity. The cocrystal structure of 216 bound to fXa (PDB code 1MQ5) revealed that the molecule adopts the characteristic L-shaped conformation of fXa inhibitors, with the chlorophenyl moiety bound to S1 and the piperazine moiety located at the S4 pocket.…”

Section: Factor Xa Inhibitors For Thromboembolic Disorders K 247mentioning

confidence: 95%

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: Factor Xa Inhibitors For Thromboembolic Disorders K 247mentioning

confidence: 95%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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“…Suzuki couplings of S-heterocyclic aryl chlorides: Thiophenes and N,S-heterocyclic thiazoles are abundant in natural products, and many compounds bearing thiophene moieties are of interest in pharmaceutical and fine chemistry, due to their biological activities. [20,100,101,[102][103][104][105][106][107][108][109][110] Aryl derivatives of benzothiazole have attracted interest due to their biological activities as glutamate receptor antagonists. [28] There are a few reports on Suzuki couplings of chlorothiophenes in the presence of catalyst loadings of 1-2 mol %.…”

Section: Suzuki Cross-coupling Of N-heterocyclesmentioning

confidence: 99%

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Fleckenstein

Plenio

2008

Chemistry A European J

120

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A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl)phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na(2)PdCl(4)] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridine- or indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol % of Pd catalyst at 100 degrees C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol % of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).

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“…4 Thiophene/benzothiophene-substituted anthranilamides (2) have been reported as novel and potent inhibitors of human fXa. 5 Anthranilamide-based N,N-dialkylamidines have been reported to be orally available potent inhibitors of fXa. 6 Darexaban (YM150), a 1,4-diazepanylbenzamide (3), has been claimed to be a potent and orally bioavailable fXa inhibitor.…”

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confidence: 99%

Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents

Verma

Giridhar

Kanhed

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:In an effort to develop potent antithrombotic agents, a series of novel 2-aminobenzamide derivatives were synthesized and screened for their in vivo antithrombotic activity. Among the 23 compounds tested, compound (8g) showed the most promising antithrombotic activity, which was comparable with clinically used aspirin or warfarin, but at variance with these standard drugs, 8g did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent.

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Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa

Cited by 25 publications

References 47 publications

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents

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