- Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
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Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.
- Bassetto, Marcella,Brancale, Andrea,Pasqualetto, Gaia,Pileggi, Elisa,Rozanowska, Malgorzata,Schepelmann, Martin,Varricchio, Carmine
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supporting information
(2021/09/24)
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- Discovery of a selective S1P1 receptor agonist efficacious at low oral dose and devoid of effects on heart rate
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Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P 1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy] phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl] propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.
- Demont, Emmanuel H.,Andrews, Benjamin I.,Bit, Rino A.,Campbell, Colin A.,Cooke, Jason W. B.,Deeks, Nigel,Desai, Sapna,Dowell, Simon J.,Gaskin, Pam,Gray, James R. J.,Haynes, Andrea,Holmes, Duncan S.,Kumar, Umesh,Morse, Mary A.,Osborne, Greg J.,Panchal, Terry,Patel, Bela,Perboni, Alcide,Taylor, Simon,Watson, Robert,Witherington, Jason,Willis, Robert
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supporting information; experimental part
p. 444 - 449
(2011/08/08)
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- Discovery of a brain-penetrant S1P3-sparing direct agonist of the S1P1 and S1P5 receptors efficacious at low oral dose
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2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on
- Demont, Emmanuel H.,Arpino, Sandra,Bit, Rino A.,Campbell, Colin A.,Deeks, Nigel,Desai, Sapna,Dowell, Simon J.,Gaskin, Pam,Gray, James R. J.,Harrison, Lee A.,Haynes, Andrea,Heightman, Tom D.,Holmes, Duncan S.,Humphreys, Philip G.,Kumar, Umesh,Morse, Mary A.,Osborne, Greg J.,Panchal, Terry,Philpott, Karen L.,Taylor, Simon,Watson, Robert,Willis, Robert,Witherington, Jason
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supporting information; experimental part
p. 6724 - 6733
(2011/12/04)
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- S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING
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The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 170
(2010/12/31)
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- BASIC AMINE COMPOUND AND USE THEREOF
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Novel amine compounds which are represented by the following formula (1) and efficacious against diseases such as a viral infectious disease with HIV, rheumatism, and cancer metastasis; typically, A 1 and A 2 represent a hydrogen atom or a substitutable monocyclic or polycyclic heteroaromatic ring and W represents a substitutable benzene ring or any group represented by the following formula (10) or (11): where X represents O, CH 2 , C(=O), NR 11 , or CHR 35 and D represents a group represented by the following formula (6): where Q represents a single bond, NR 12 , or a group represented by the formula (13): and Y represents a group represented by the following formula (7) : where z represents a substitutable monocyclic or polycyclic aromatic ring; and B represents -NR 25 R 26 ; and R 1 to R 26 in the above formulae represent a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group.
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Page/Page column 41
(2010/11/24)
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- Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors
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Compounds of formula (I): wherein: R1 represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-4alkyl, C1-4
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Page/Page column 7
(2008/06/13)
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- Spirocycles
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Compounds of the general formula: STR1 or a pharmaceutically acceptable salt, hydrate or crystal form enantiomer, diastereomer or mixtures thereof are Class III antiarrhythmic agents.
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