Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors. 2

Quan, Mimi L.; Ellis, Christopher D.; Liauw, Ann Y.; Alexander, Richard; Knabb, Robert M.; Lam, Gilbert N.; Wright, Matthew; Wong, Pancras C.; Wexler, Ruth R.

doi:10.1021/jm980406a

Cited by 81 publications

(36 citation statements)

References 21 publications

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“…Ki values are averaged from multiple determinations (n ¼ 2), and the standard deviations are < 30% of the mean. Ki were measured as in reference [13,14] ) of human fXa inhibitors are extracted from the literature [6 -8]. All the structures and data are listed in Table 1, which are used to construct activity model.…”

Section: Data Setsmentioning

confidence: 99%

Comparative Study of Factor Xa Inhibitors Using Molecular Docking/SVM/HQSAR/3D‐QSAR Methods

Sun¹,

Chen²,

Xia³

et al. 2006

QSAR Comb. Sci.

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The binding modes of a group of Factor Xa (fXa) inhibitors were studied using FlexX. CoMFA, CoMSIA, HQSAR and SVM models for inhibition potency were constructed with the conformers obtained from the molecular docking. 3D-QSAR models for oral biovailability were also constructed with the subset inhibitors. The results show that these models possess good prediction ability. The influence of substituents for the activity and oral bioavailability were explored by comparing the constructed 3D-QSAR models. We found that some substituents have consistent effects on inhibition potency and oral bioavailablity, but some have inconsistent effects. We observed equally that the different methods involved in this study, such as molecular docking, SVM, HQSAR and 3D-QSAR models, could be used not only for the prediction, but they are also complementary each to other. They are helpful for better understanding the interaction mechanism between inhibitors and fXa receptor.

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Section: Data Setsmentioning

confidence: 99%

Comparative Study of Factor Xa Inhibitors Using Molecular Docking/SVM/HQSAR/3D‐QSAR Methods

Sun¹,

Chen²,

Xia³

et al. 2006

QSAR Comb. Sci.

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“…77 To date very few monobasic FXa inhibitors have been reported. Ellis and co-workers 77 have reported their effort on synthesizing a series of bisbenzamidine isoxazoline derivatives and a series of monobasic substituted biaryl isoxazoline derivatives.…”

Section: Bisbenzamidine Isoxazoline and Monobasic Substituted Biaryl mentioning

confidence: 99%

Current trends in quantitative structure activity relationships on FXa inhibitors: Evaluation and comparative analysis

Kontogiorgis¹,

Hadjipavlou‐Litina²

2004

Medicinal Research Reviews

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This article evaluates the quantitative structure activity relationships of FXa inhibitors, using the C-QSAR program of Biobyte. Diaryloxypyridines, aminophenols, biaryl isoxazoline derivatives, 1,2-dibenzamidobenzenes, 3-amidinophenylalanine derivatives, benzoxazinones, naphthoanilides, tetrazoles, glucolic and mandelic acid derivatives were included in this survey. Clog P plays a significant role in the QSAR, especially as hydrophilicity. In the most of the cases, CMR/MR molar refractivity as well as sterimol parameters (B5 and L) are important. Electronic effects with the exception of the Hammett's constant sigmam, are not found to govern the biological activity. Es was found to be important indicator variables were used after the best model was found to account for the usual structural features.

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“…A systematically large number of research disclosed that 3,5-diaryl-5-(trifluoromethyl)-2-isoxazoline unit 1 is a key skeleton for its biological activity [36][37][38]. Since 2010, our group has also made contributions to this fascinating structure by the direct late-stage trifluoromethylation of aromatic isoxazoles with Ruppert-Prakash reagent (trifluoromethyl) trimethylsilane (Me 3 SiCF 3 ) [39][40]41], and a fluorinated building block strategy based on the use of inexpensive reagents under organocatalysis with an eye on industrial purposes [36][37][38]. We are now interested in the synthesis of difluoromethyl analogs of this key structure, i.e., 3,5-diaryl-5-(difluoromethyl)-2-isoxazolines 2.…”

Section: Introductionmentioning

confidence: 99%

Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl)trimethylsilane

Wang,

Tokunaga,

Shibata

2014

ScienceOpen Research

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The activation of aromatic diaryl isoxazoles with strong electron-withdrawing groups, such as the nitro, triflyl, and the phenylsulfonyl groups, at the 4-position has enabled the first regio-and diastereoselective difluoromethylation at the 5-position of isoxazoles by nucleophilic addition using (difluoromethyl) trimethylsilane, Me 3 SiCF 2 H, to provide difluoromethylated isoxazolines in good yields. Conjugated styryl-4-nitroisoxazoles were also nicely converted into the corresponding CF 2 H adducts with high regio-and excellent diastereoselectivities. Since the trifluoromethylated analogs of the corresponding diaryl-isoxazolines are effective ectoparasiticides, represented by fluralaner, should a series of difluoromethylated isoxazolines be obtained, they would be of great importance as promising drug candidates in this field.Heterocycles have an extensive history and are present in a wide variety of drugs, most vitamins, many natural products, biomolecules, and biologically active compounds [1][2][3][4]. Manmade fluorinated organic compounds have become a remarkable success in the pharmaceutical industry, despite their relatively young history [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In this context, fluorinated heterocycles have gained attention as new drug candidates over the past few decades in medicine and agro-chemistry [21][22][23][24][25][26][27][28]. Fluorinated and trifluoromethylated compounds have been well targeted in this research area [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], and difluoromethylated compounds are next [16,[21][22][23][24][25][26][27][28]. The difluoromethyl (CF 2 H) group is known to be isosteric and isopolar to a hydroxy (OH) and thiol (SH) unit. The CF 2 H group can also act as a more lipophilic hydrogen donor than OH and NH groups through hydrogen bonding [31][32][33][34]. Thus, the difluoromethylation of biologically active molecules is an effective strategy for the design new candidates of pharmaceuticals and agrochemicals [16]. BRAVECTO™ (fluralaner) is a highly potent insect and acarid RDL and GluCl inhibitor that was just recently approved in chewable tablets for dogs against fleas and ticks [35]. A systematically large number of research disclosed that 3,5-diaryl-5-(trifluoromethyl)-2-isoxazoline unit 1 is a key skeleton for its biological activity [36][37][38]. Since 2010, our group has also made contributions to this fascinating structure by the direct late-stage trifluoromethylation of aromatic isoxazoles with Ruppert-Prakash reagent (trifluoromethyl) trimethylsilane (Me 3 SiCF 3 ) [39][40]41], and a fluorinated building block strategy based on the use of inexpensive reagents under organocatalysis with an eye on industrial purposes [36][37][38]. We are now interested in the synthesis of difluoromethyl analogs of this key structure, i.e., 3,5-diaryl-5-(difluoromethyl)-2-isoxazolines 2. More than 27,000 isoxazolines 1 with a quaternary carbon bearing a CF 3 group at the 5-position have been s...

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Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors. 2

Cited by 81 publications

References 21 publications

Comparative Study of Factor Xa Inhibitors Using Molecular Docking/SVM/HQSAR/3D‐QSAR Methods

Comparative Study of Factor Xa Inhibitors Using Molecular Docking/SVM/HQSAR/3D‐QSAR Methods

Current trends in quantitative structure activity relationships on FXa inhibitors: Evaluation and comparative analysis

Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl)trimethylsilane

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