- Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor
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Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.
- Granchi, Carlotta,Lapillo, Margherita,Glasmacher, Sandra,Bononi, Giulia,Licari, Cristina,Poli, Giulio,El Boustani, Maguie,Caligiuri, Isabella,Rizzolio, Flavio,Gertsch, Jürg,Macchia, Marco,Minutolo, Filippo,Tuccinardi, Tiziano,Chicca, Andrea
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p. 1932 - 1958
(2019/02/26)
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- ANILINE DERIVATIVES,THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
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The present invention relates to aniline derivatives, to their preparation and to their therapeutic application.
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Page/Page column 61; 62
(2013/03/28)
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- Palladium-catalyzed aryl-aryl cross-coupling reaction using ortho-substituted arylindium reagents
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(Chemical Equation Presented) A range of biaryl compounds (aryl-aryl, aryl-heteroaryl, and heteroaryl-heteroaryl) can be efficiently prepared by a palladium-catalyzed cross-coupling reaction between ortho-substituted triarylindium reagents and aryl halide
- Pena, Miguel A.,Sestelo, Jose Perez,Sarandeses, Luis A.
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p. 1271 - 1275
(2007/10/03)
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- 2,3-DIHYDRO-ISOINDOL-1-ONES WITH MAO-B INHIBITING ACTIVITY
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2,3 Dihydro-isoindol-1-one derivatives, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them, for the prevention and treatment of diseases which are mediated by monoamine oxidase B inhibitors.
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- 3-(3-aryloxyphenyl)-1-(substituted methyl)-s-triazine-2,4,6-oxo or thiotrione herbicidal agents
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There is provided a 3-(3-aryloxyphenyl)-1-(substituted methyl)-s-triazine-2,4,6-oxo or thiotrione compound having the structural formula I STR1 Further provided are a composition and a method comprising that compound for the control of undesirable plant s
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- NEW COMPOUNDS
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The present invention relates to novel derivatives of 3-hydroxyanthranilic acid, 3-HANA, of the general formula I wherein R1 and R2 are the same or different and selected from H, alkyl, aryl and arylalkyl; X and Y are the same or different and selected fr
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- CHROMAN DERIVATIVES
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3-amino-5-carbamoylchromans and 8-fluoro-3-amino-5-carbamoylchromans, as well as enantiomers and salts thereof, are disclosed. Pharmaceutical compositions containing the compounds as active ingredients are also disclosed. The compounds are useful in the treatment of 5-hydroxytryptamine-mediated disorders of the central nervous system.
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- Fluorine as an ortho-directing group in aromatic metalation: Generality of the reaction and the high position of fluorine in the Dir-Met potency scale
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Many para-substituted fluorobenzenes can be lithiated ortho to fluorine in moderate to good yields, often with one of the dialkylamide bases, lithium diisopropylamide (LDA) or lithium 2,2,6,6-tetramethylpiperidide (LiTMP). Intramolecular competition experiments reveal that fluorine is one of the most potent Dir-Met activating groups under these conditions.
- Bridges,Lee,Maduakor,Schwartz
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p. 7495 - 7498
(2007/10/02)
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- Ring-substituted 1,2-dialkylated 1,2-bis(hydroxyphenyl)ethanes. 2. Synthesis and estrogen receptor binding affinity of 4,4'-, 5,5'-, and 6,6'-disubstituted metahexestrols
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The synthesis of symmetrically 4,4'-, 5,5'-, and 6,6'-disubstituted derivatives of the mammary tumor inhibiting antiestrogen metahexestrol [meso-3,4-bis(3-hydroxyphenyl)hexane] (1) are described [4,4'-disubstituents: F(2), Cl (3), Br (4), I (5), CH2N(CH3)2 (6), CH3 (7), CH2OCH3 (8), CH2OC2H5 (9), CH2OH (10), NO2 (11), NH2 (12), N(CH3)2 (13), COCH3 (14), and C2H5 (15); 5,5'-substituents: OH (16) and Cl (17); 6,6'-disubstituents: OH (18), F (19), Cl (20), and CH3 (21)]. The synthesis of 1-3, 16, and 19 was accomplished by reductive coupling of the propiophenones with TiCl4/Zn and subsequent hydrogenation of the cis-3,4-diphenylhex-3-enes. Compounds 17, 18, 20, and 21 were synthesized by coupling the 1-phenyl-1-propanols with TiCl3/LiAlH4 and separation of the meso diastereomers, while 4-15 were obtained by substitution of metahexestrol. The binding affinity of these compounds to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. The test compounds showed relative binding affinity (RBA) values between 15 and 0.5% were evaluated in the mouse uterine weight test. They showed a similar (2 and 12), slightly increased (19 and 21), or strongly enhanced (7 and 20) estrogenicity compared to that of metahexestrol. Compounds 1, 2, 7, 12, and 21 exhibited antiestrogenic activity inhibiting the estrone-stimulated uterine growth (24 to 60% inhibition).
- Hartmann,Heindl,Schonenberger
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p. 577 - 585
(2007/10/02)
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