- Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation
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We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.
- Ohe, Tomoyuki,Umezawa, Ryutaro,Kitagawara, Yumina,Yasuda, Daisuke,Takahashi, Kyoko,Nakamura, Shigeo,Abe, Akiko,Sekine, Shuichi,Ito, Kousei,Okunushi, Kentaro,Morio, Hanae,Furihata, Tomomi,Anzai, Naohiko,Mashino, Tadahiko
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supporting information
p. 3708 - 3711
(2018/11/02)
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- Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides
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Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantioselective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatilit
- Miyaji, Ryota,Wada, Yuuki,Matsumoto, Akira,Asano, Keisuke,Matsubara, Seijiro
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supporting information
p. 1518 - 1523
(2017/08/14)
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- COMBINATION THERAPIES FOR TREATMENT OF CANCER
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Combination therapies for treatment of cancers associated with mutations in the KRAS gene are provided. Compositions comprising therapeutic agents for treatment of cancers associated with mutations in the KRAS gene are also provided.
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- Use of Inhibitors of the Activity or Function of PI3K
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The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.
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Paragraph 0869-0870
(2016/01/09)
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- COVALENT INHIBITORS OF KRAS G12C
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Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.
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- QUINAZOLINE DERIVATIVES AS PI3K MODULATORS
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The invention relates to substituted quinazoline derivative of the formula (I), wherein A, X1, X2, X3, X4 and R5 are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of the PI3K enzymes.
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Page/Page column 52-53
(2013/05/09)
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- Use of inhibitors of the activity or function of PI3K
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The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.
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Page/Page column 99
(2013/07/05)
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- AMIDE COMPOUNDS, COMPOSITIONS AND USES THEREOF
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Compounds are provided according to formula (1 ) : where A, B, W, X', L, R1, R3, R4b, and m' are as defined herein. Provided compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, cognitive disorders, anxiety, depression, and others.
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Page/Page column 109-110
(2009/10/22)
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- DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS
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The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
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- Dual Pharmacophores - PDE4-Muscarinic Antagonistics
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The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.
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Page/Page column 50
(2009/08/18)
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- Dual Pharmacophores - PDE4-Muscarinic Antagonistics
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The present invention relates to novel compounds of Formula (I) and their use in the treatment of respiratory diseases, including anti-inflammatory and allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
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Page/Page column 53
(2009/08/18)
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- Dual Pharmacophores - PDE4-Muscarinic Antagonistics
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The present invention is directed to novel compounds of Formula (I), pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of/and or prophylaxis of respiratory diseases, including antiinflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
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Page/Page column 53
(2009/08/16)
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- Substituted Diphenylethers, -Amines, -Sulfides and -Methanes for the Treatment of Respiratory Disease
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The invention relates to substituted diphenylethers, -amines, -sulfides, and -methanes as useful pharmaceutical compounds for treating respiratory-disorders, pharmaceutical compositions containing them, and processes for their preparation.
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Page/Page column 41
(2009/01/20)
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- Substituted 6-phenyl-2-naphthols. Potent and selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): Design, synthesis, biological evaluation, and pharmacokinetics
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17β-Estradiol (E2) is implicated in the genesis and the development of estrogen-dependent diseases. Its concentration is mainly regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent E2. This enzyme is thus an important target for the treatment of hormone-dependent diseases. Thirty-seven novel substituted 6-phenyl-2-naphthols were synthesized and evaluated for 17β-HSD1 inhibition, selectivity toward 17β-HSD2 and the estrogen receptors (ERs) α and β, and pharmacokinetic properties. SAR studies revealed that the compounds most likely bind according to binding mode B to the active site, i.e., the 6-phenyl moiety mimicking the steroidal A-ring. While substitution at the phenyl ring decreased activity, introduction of substituents at the naphthol moiety led to highly active compounds, especially in position 1. The 1-phenyl compound 32 showed a very high inhibitory activity for 17β-HSD1 (IC50 = 20 nM) and good selectivity (17β-HSD2 and ERs) and pharmacokinetic properties after peroral application.
- Marchais-Oberwinkler, Sandrine,Krachten, Patricia,Frotscher, Martin,Ziegler, Erika,Neugebauer, Alexander,Bhoga, Umadevi,Bey, Emmanuel,Müller-Vieira, Ursula,Messinger, Josef,Thole, Hubert,Hartmann, Rolf W.
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supporting information; experimental part
p. 4685 - 4698
(2009/07/19)
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- NOVEL COMPOUNDS
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The invention relates to substituted phenylacetic acids as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.
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Page/Page column 65
(2008/06/13)
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- Binding and preliminary evaluation of 5-hydroxy- and 10-hydroxy- 2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as dopamine receptor ligands
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The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10- hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D1-like and D2-like subtypes. All compounds showed very low D1 affinities. This could be ascribed to the absence of a catechol nucleus or of the β-phenyldopamine pharmacophore. Only the N-methyl-5- hydroxy- (5a), N-methyl-10-hydroxy-(6a), and N-methyl-4-bromo-10-methoxy- 2,3,12,12a-tetrahydro-1H-[1]-benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D2 receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)-ethylamine moiety does not meet the requirements of the D2 agonist pharmacophore: namely, the 2-(3- hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D4 receptors, and only 5a showed low affinity for rat recombinant D3 receptors. Analysis of the influence of Na+ on [3H]spiperone binding showed that 5a displays a potential dopamine D2 agonist profile, whereas 6a probably has a dopamine D2 antagonist activity. The D2 agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells.
- Claudi, Francesco,Di Stefano, Antonio,Napolitani, Fabrizio,Cingolani, Gian Mario,Giorgioni, Gianfabio,Fontenla, Josè A.,Montenegro, Gisela Y.,Rivas, Maria E.,Rosa, Elizabeth,Michelotto, Barbara,Orlando, Giustino,Brunetti, Luigi
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p. 599 - 608
(2007/10/03)
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