- RAR-ALPHA COMPOUNDS FOR INFLAMMATORY DISEASE AND MALE CONTRACEPTION
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Modulators of retinoid acid receptor-alpha (RARα) of formula (I) are provided herein, as well as pharmaceutical compositions and methods relating thereto.
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Paragraph 0107
(2021/06/26)
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- Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound
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Retinoic acid receptor alpha (RARα) selective compounds may guide the design of drugs that can be used in conjunction with hormonal adjuvant therapy in the treatment of breast cancer. Herein we report a modified synthesis of a known RARα antagonist, 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4- methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid and a synthesis of its unknown, desfluoro analog, 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman- 6-yl]carbonyl]amino]benzoic acid. The modified route allows for facile reaction workups, increased yields, lower cost and incorporates a green alternative step. Structure-activity relationship studies determined through functional cell-based assays, demonstrated antagonism to RARα for both compounds. Molecular modeling within the RARα binding pocket was used to compare binding interactions of the desfluoro analog to a known RAR antagonist.
- Jetson, Rachael,Malik, Neha,Luniwal, Amarjit,Chari, Venkatesh,Ratnam, Manohar,Erhardt, Paul
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supporting information
p. 104 - 108
(2013/07/27)
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- GPR120 RECEPTOR AGONISTS AND USES THEREOF
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GPR120 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.
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Page/Page column 86
(2012/01/06)
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- GPR120 RECEPTOR AGONISTS AND USES THEREOF
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GPR120 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.
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Page/Page column 26
(2012/01/13)
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- Reductive lithiation of cyclic benzofused ethers: A source of oxygen-functionalised organolithium compounds
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The reaction of 2,3-dihydrobenzofuran (1) with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 5%) in THF at 0°C for 1.5h, followed by addition of an electrophile [E+=H2O, tBuCHO, PhCH2CHO, Ph(CH2)2CHO, PhCHO, furfural, Me2CO, Et2CO, cyclopentanone, cyclohexanone, cyclooctanone, (-)-menthone] in THF at -78°C gives, after hydrolysis, compounds 3. Some diols 3 are easily transformed into 2-substituted chromans 6 under acidic reaction conditions. The reductive lithiation of chroman (7) at 20°C for 3h leads exclusively to the intermediate 8, which is formed through a dearylation process, and isomerises to the apparently more stable benzylic intermediate 9. The reaction of these intermediates with different electrophiles {E+=tBuCHO, PhCHO, furfural, Me2CO, [CH3(CH2)4]2CO, cyclopentanone, cyclohexanone, (-)-menthone, Ph2CO}, at -78°C in THF leads, after hydrolysis, to a mixture of regioisomers 10 and 11. The reaction of 2,3-benzofuran (12) with an excess of lithium and a catalytic amount of DTBB (5%) in THF at 0°C for 45min leads to dianionic intermediate 13 through a dealkylation process, which after hydrolysis gives 2-vinylphenol 14. In the case of 4H-chromene (15), reductive opening is performed at 20°C for 45min, a mixture of dearylation and dealkylation intermediates 16 and 17, respectively, is obtained (2:1 ratio) giving, after hydrolysis, 3-phenylpropanal (18) and 2-allylphenol (19).
- Yus, Miguel,Foubelo, Francisco,Ferrández, José V,Bachki, Abderrazak
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p. 4907 - 4915
(2007/10/03)
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- Addition of trialkylaluminum reagents to glyconolactones. Synthesis of 1-C-methyl GlcNAc oxazoline and thiazoline
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Addition of carbon nucleophiles to 2-acetamido-2-deoxygluconolactones fails for many reagents, but trialkylaluminums add alkyl smoothly. The product of methyl addition to 2-acetamido-2-deoxy-D-gluconolactone has been converted to 1-C-methyl GlcNAc thiazoline, a potential N-acetylhexosaminidase inhibitor, and to an O-protected 1-C-Me GlcNAc oxazoline, a potential 1-C-Me GlcNAc donor.
- Knapp, Spencer,Yang, Chunhua,Haimowitz, Thomas
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p. 7101 - 7104
(2007/10/03)
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- Organolithium reagents from alkyl phenyl ethers
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The reaction of primary alkyl or vinyl phenyl ethers (1) as well as 2,3- dihydrobenzofuran (3) with an excess of lithium powder and a catalytic amount of DTBB (5 %) in THF at room temperature leads to the corresponding organolithium intermediates, which by treatment with different electrophiles [H2O, D2O, Me3SiCl, Bu(t)CHO, PhCHO, Me2CO, Et2CO, (CH2)4CO, (CH2)5CO, PhCOMe] and final hydrolysis affords the expected products 2 and 4.
- Bachki, Abderrazak,Foubelo, Francisco,Yus, Miguel
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p. 7759 - 7762
(2007/10/03)
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- Identification of highly potent retinoic acid receptor α-selective antagonists
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The syntheses and full retinoid receptor characterization of a novel series of retinoic acid receptor α (RARα) antagonists, 1-5, are described. These compounds bind with high affinity to RARα but were completely inactive in gene transactivation. They were also potent and effective antagonists of retinoic acid (RA) induced gene transcription at RARα. Compounds 1-5 exhibited varying degrees of selectivity for RARα relative to RARβ/γ, with compound 5 being the most selective in both binding and functional antagonism assays. These compounds will be invaluable tools in delineating the physiological roles of RARα in development and in the adult animal and may themselves be useful therapeutic agents in human diseases associated with RARα.
- Teng, Min,Duong, Tien T.,Johnson, Alan T.,Klein, Elliott S.,Wang, Liming,Khalifa, Berket,Chandraratna, Roshantha A. S.
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p. 2445 - 2451
(2007/10/03)
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- REGIOSELECTIVE PRENYLATION OF PHENOLS BY PALLADIUM CATALYST: SYNTHESES OF PRENYLPHENOLS AND CHROMANS
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The palladium-catalyzed coupling reaction of iodophenols (1) with 2-methyl-3-butyn-2-ol gave alkynylphenols (2).Catalytic hydrogenation of 2 over Raney nickel and the subsequent dehydration of the resultant alkylphenols (3) gave regioselectively the desired prenylphenols (4).Dehydration of alkylphenols (3f-h) gave chromans (7).
- Tsukayama, Masao,Kikuchi, Makoto,Kawamura, Yasuhiko
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p. 1487 - 1490
(2007/10/02)
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- Chroman esters of phenols and benzoic acids having retinoid-like activity
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Retinoid like activity is exhibited by compounds of the formula STR1 wherein the R 1 -R 7 groups are independently H or straight chain or branched chain lower alkyl or cycloalkyl of 1 to 6 carbons; X symbolizes an ester or thioester linkage, Y is cycloalk
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- Synthetic and Stereochemical Studies of the Octahydro-1-benzopyran System
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The cis and trans isomers of the octahydro-1-benzopyran system have been synthesised and their conformations studied by low-temperature (13)C and highfield (1)H n.m.r. spectroscopy.The position of the conformational equilibrium in the cis isomer at -70 deg C in CDCl3-CFCl3 (50:50) has been determined as approximately 99.5:0.5 (ΔG0 -8.9 kJ mol-1) in favour of the conformation having the oxygen axially disposed towards the cyclohexane ring.
- Griffiths, D. Vaughan,Wilcox, Geoffrey
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p. 431 - 436
(2007/10/02)
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- Design, synthesis, and testing of potential antisickling agents. 10. (2,2-Dimethylchroman-6-yl)alkanoic acids
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Five (2,2-dimethylchroman-6-yl)alkanoic acids were synthesized and tested for antigelling activities. It was envisioned that these agents might bind via hydrophobic bonding to nonpolar sites of the 'donor-acceptor' regions of hemoglobin S. Several (2,2-di
- Fatope,Abraham
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p. 1973 - 1977
(2007/10/02)
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