- QUINAZOLINE DERIVATIVE AND USE THEREOF
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The present invention relates to a series of quinazoline compounds, especially compounds as represented by formula (I), isomers thereof or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and use thereof as Pan-HER tyrosine kinase inhibitors.
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Paragraph 0217-0219
(2020/11/26)
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- PYRAZOLE-CONTAINING MACROPHAGE MIGRATION INHIBITORY FACTOR INHIBITORS
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In one aspect, the invention comprises compounds that bind and inhibit macrophage migration inhibitory factor. In another aspect, the invention provides methods of treating inflammatory disease, neurological disorders and cancer using the compounds of the invention.
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Page/Page column 115
(2019/10/04)
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- Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor
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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto–enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113-μm docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60–70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl–aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.
- Trivedi-Parmar, Vinay,Robertson, Michael J.,Cisneros, José A.,Krimmer, Stefan G.,Jorgensen, William L.
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supporting information
p. 1092 - 1097
(2018/04/30)
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- BIARYLTRIAZOLE INHIBITORS OF MACROPHAGE MIGRATION INHIBITORY FACTOR
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The present disclosure describes biaryl triazole compounds, as well as their compositions and methods of use. The compounds inhibit the activity of macrophage migration inhibitory factor and are useful for the treatment of diseases, e.g., inflammatory dis
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Page/Page column 171
(2016/09/22)
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- Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor
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Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl-aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.
- Dziedzic, Pawel,Cisneros, José A.,Robertson, Michael J.,Hare, Alissa A.,Danford, Nadia E.,Baxter, Richard H. G.,Jorgensen, William L.
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supporting information
p. 2996 - 3003
(2015/03/18)
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- NOVEL BETULINIC ACID DERIVATIVES AS HIV INHIBITORS
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(I)The invention relates to novel novel betulinic acid derivatives and related compounds, and pharmaceutical compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Paragraph 0259
(2013/11/18)
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- Unsymmetrical non-adamantyl N,N′-diaryl urea and amide inhibitors of soluble expoxide hydrolase
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Incorporation of an adamantyl group in prototypical soluble expoxide hydrolase (sEH) inhibitors afforded improved enzyme potency. We explored replacement of the adamantyl group in unsymmetrical ureas and amides with substituted aryl rings to identify equipotent and metabolically stable sEH inhibitors. We found that aryl rings, especially those substituted in the para position with a strongly electron withdrawing substituent, afforded enzyme IC50 values comparable to the adamantyl compounds in an ether substituted, unsymmetrical N,N′-diaryl urea or amide scaffold.
- Anandan, Sampath-Kumar,Webb, Heather K.,Do, Zung N.,Gless, Richard D.
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scheme or table
p. 4259 - 4263
(2010/04/26)
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- BIOACTIVE COMPOUNDS FOR TREATMENT OF CANCER AND NEURODEGENERATIVE DISEASES
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The invention provides bioactive compounds for the treatment of various malconditions such as cancer and neurodegenerative diseases including Alzheimer's disease. The chemical compounds as disclosed herein are found to show bioactivity in bioassays related to these conditions. Pharmaceutical compositions, combinations and methods of synthesis are provided, as are methods of using the compound, compositions and combinations in the treatment of the diseases.
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Page/Page column 81
(2009/12/23)
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- SOLUBLE EPOXIDE HYDROLASE INHIBITORS
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Disclosed are urea and thiourea compounds and compositions that inhibit soluble epoxide hydrolase (sEH), methods for preparing the compounds and compositions, and methods for treating patients with such compounds and compositions. The compounds, compositions, and methods are useful for treating a variety of sEH mediated diseases, including hypertensive, cardiovascular, inflammatory, and diabetic-related diseases.
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Page/Page column 69-70
(2008/12/07)
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- 1,3-Disubstituted ureas functionalized with ether groups are potent inhibitors of the soluble epoxide hydrolase with improved pharmacokinetic properties
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Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation.
- Kim, In-Hae,Tsai, Hsing-Ju,Nishi, Kosuke,Kasagami, Takeo,Morisseau, Christophe,Hammock, Bruce D.
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p. 5217 - 5226
(2008/03/13)
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