- COMPOUNDS AND METHODS OF TREATING OCULAR DISORDERS
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A method of treating an ocular disorder in a subject associated with increased all-trans-retinal in an ocular tissue includes administering to the subject a therapeutically effective amount of a primary amine compound of formula (I); and pharmaceutically acceptable salts thereof.
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Paragraph 00181
(2016/06/14)
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- Expansion of first-in-class drug candidates that sequester toxic all-trans-retinal and prevent light-induced retinal degeneration
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All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.
- Zhang, Jianye,Dong, Zhiqian,Mundla, Sreenivasa Reddy,Hu, X. Eric,Seibel, William,Papoian, Ruben,Palczewski, Krzysztof,Golczak, Marcin
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supporting information
p. 477 - 491
(2015/01/30)
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- New syntheses of retinal and its acyclic analog γ-retinal by an extended aldol reaction with a C6 building block that incorporates a C5 unit after decarboxylation. A formal route to lycopene and β-carotene
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Since the C15 β-end-group aldehyde 10 ((β-ionylidene) acetaldehyde), an excellent intermediate in the syntheses of retinoids, can be synthesized in many ways from β-ionone, and since the corresponding acyclic C15 ψ-end-group aldehyde 5 can easily be synthesized from citral (1) (Scheme 3), we applied the C15 + C5 route to the syntheses of γ-retinal ((all-E)-8) (Scheme 3) and retinal ((all-E)-13) (Scheme 4), and therefore, by coupling (2 x C20 → C 40), to the preparation of lycopene (14) and β-carotene (15) (Scheme 5). Our new syntheses of retinal ((all-E)-13) and γ-retinal ((all-E)-8 use an extended aldol reaction with a C6 building block that incorporates a C5 unit after decarboxylation.
- Valla, Alain,Valla, Benoist,Le Guillou, Regis,Cartier, Dominique,Dufosse, Laurent,Labia, Roger
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p. 512 - 520
(2008/02/07)
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- Perrhenic acid-catalyzed dehydration from primary amides, aldoximes, N-monoacylureas, and α-substituted ketoximes to nitrile compounds
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The dehydration reaction of primary amides is one of the most fundamental methods for the synthesis of nitriles, and the development of environmentally benign catalytic reaction processes is needed. We surveyed a variety of metal catalysts and found that perrhenic acid was extremely effective for the dehydration of not only primary amides but also aldoximes. Typically, 1 mol % of perrhenic acid gave the corresponding nitriles from amides or aldoximes under azeotropic reflux conditions with the removal of water in toluene or mesitylene. In addition, perrhenic acid is an extremely efficient catalyst for the Beckmann fragmentation of α-substituted ketoximes to functionalized nitriles. This new catalytic system can be applied to the gram-scale synthesis of nitriles without further modifications.
- Furuya, Yoshiro,Ishihara, Kazuaki,Yamamoto, Hisashi
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p. 400 - 406
(2008/02/11)
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- Rhenium(VII) oxo complexes as extremely active catalysts in the dehydration of primary amides and aldoximes to nitriles
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An economical and environmentally benign process for the preparation of nitriles by the dehydration of primary amides and aldoximes is catalyzed by rhenium(VII) oxo complexes such as perrhenic acid and trimethylsilylperrhenate (see scheme). The reaction proceeds at azeotropic reflux (with the removal of water) under essentially neutral conditions.
- Ishihara, Kazuaki,Furuya, Yoshiro,Yamamoto, Hisashi
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p. 2983 - 2986
(2007/10/03)
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- Highly efficient and catalytic conversion of aldoximes to nitriles
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(Matrix Presented) Catalytic dehydration of aldoximes can be performed highly efficiently with a catalyst system of [RuCl2(p-cymene)]2/molecular sieves under essentially neutral and mild conditions, and various types of cyano compounds are produced in good to excellent yields.
- Yang, Soon Ha,Chang, Sukbok
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p. 4209 - 4211
(2007/10/03)
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- Synthesis and Antitumor Activity of Retinoids with Modified Polar Head. Communication I
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Several retinoids with a modified polar group were synthesized.Biological screening using HL-60 promyelocyte leukemia cells showed that the free carboxyl in the retinoid molecules is not the only group responsible for exhibiting the differentiating activi
- Deryabina, E. L.,Khodonov, A. A.,Cherevataya, G. V.,Kirillova, Yu. G.,Shvets, V. I.,et al.
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p. 811 - 818
(2007/10/03)
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- Synthesis of (12,13-(13)C2)retinal and (13,14-(13)C2)retinal: a strategy to prepare multiple-(13)C-labeled conjugated systems
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(12,13-(13)C2)Retinal, (13,14-(13)C2)retinal, (19-(13)C)retinal and (20-(13)C)retinal (1) were prepared in a simple fashion in high yield via a consecutive strategy.The key step is the reaction of a N-methoxy-N-methylamide with an alkyllithium or a Grignard reagent.The preparation of the required N-methoxy-N-methylamide is discussed.In this scheme, only three commercially available (13)C-labeled starting materials (ethyl bromoacetate, acetonitrile and methyl iodide) are sufficient to construct retinals with any possible combination of (13)C labeling in the conjugated tail end.This strategy is applicable to the preparation of many other conjugated systems, such as retinoids, carotenoids and polyenes.
- Groesbeek, M.,Rood, G. A.,Lugtenburg, J.
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p. 149 - 154
(2007/10/02)
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- Preparation of (9Z, 11Z) - Vitamin A
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Starting from (7E,9Z)-C15-aldehyde 4, the syntheses of (9Z, 11Z)-vitamin A acetate and palmitate are reported. The construction strategy is based on treatment of 4 with Zn-PPh3/CBr4, addition of acetaldehyde followed by a
- Vogt, Peter,Schlageter, Markus,Widmer, Erich
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p. 4115 - 4116
(2007/10/02)
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- Synthesis of 8-, 9-, 12-, and 13-mono-13C-retinal
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The 8-, 9-, 12-, and 13-mono-13C-retinals were synthesized with >98percent chemical purity and 93percent 13C incorporation from 13C-labelled acetonitrile.Their 13C-13C and 13C-1H nmr coupling constants were determined.
- Pardoen, J. A.,Mulder, P. P. J.,Berg, E. M. M. van den,Lugtenburg, J.
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p. 1431 - 1435
(2007/10/02)
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- SYNTHETIC INVESTIGATIONS IN THE CHEMISTRY OF POLYENE COMPOUNDS. L. SYNTHESIS OF THE NITRILES AND HYDROXYNITRILES OF RETINOIC ACID
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Glycidonitrile was synthesized from 9-methyl-7-(1,1,5-trimethyl-5-cyclohexen-6-yl)-9,11-octadien-13-one and chloroacetonitrile by a modified Darzens reaction.Opening of the epoxide ring in the glycidonitrile gave 9,14-dihydroxy-9,13-dimethyl-7-(1,1,5-trimethyl-5-cyclohexen-6-yl)-10,12-nonadiene-15-nitrile with a yield of 70percent calculated on the ketone.Partial dehydration of the latter gave 14-hydroxy-9,13-dimethyl-7-(1,1,5-trimethyl-5-cyclohexen-6-yl)-8,10,12-nonatriene-15-nitrile - the key compound in the synthesis of the biologically active analog of the vitamin Ametabolite.The total dehydration of the dihydroxynitrile led to retinonitrile.
- Zakharova, N. I.,Gutnikova, N. P.,Bekker, A. R.,Filippova, T. M.,Miropol'skaya, M. A.,Samokhvalov, G. I.
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p. 1870 - 1874
(2007/10/02)
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- Synthesis of retinals labelled at positions 14 and 15 (with 13C and/or 2H)
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Eight retinals labelled at positions 14 and 15 with 13C and/or 2H were obtained with 98 percent chemical purity, 92 percent 13C incorporation, 95 percent 2H incorporation at position 14 and 99 percent 2H incorporation at position 15. (14-13C)retinal, (15-13C)retinal and (14,15-13C)retinal were synthesized from (2-13C)-, (1-13C)- and (1,2-13C)acetonitrile, respectively, while for the synthesis of (14-2H)retinal, 2CH3CN was used.Via a three-step process these retinals were transformed into (14,15-2H)retinal, (14-13C,15-2H)retinal, (15-13C,15-2H)retinal and (14,15-13C2,15-2H)retinal.Their 13C-13C, 13C-2H and 13C-H NMR coupling constants were determined.
- Pardoen, J. A,Winkel, C,Mulder, P.P.J,Lugtenburg, J
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p. 135 - 141
(2007/10/02)
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- A SHORT PATH SYNTHESIS OF RETINALS. SYNTHESIS OF 13C- OR 2H-LABELED RETINALS
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Trimethylsilylated acetaldehyde t-butylimine 4 was found to be an effective two carbon-homologenation reagent in the synthesis of retinals and its congeners.A short path synthesis of retinals (1 and 2) by using 4 and its application to the synthesis of 13C-labeled retinal 12 and octadeuterium retinal 27 is described.KEYWORDS - retinal; retinoid; vitamin A aldehyde; visual pigment; α,β-unsaturated aldehyde synthesis; silylated imine
- Akita, Hiroyuki
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p. 1796 - 1799
(2007/10/02)
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