- First synthesis of racemic trans propargylamino-donepezil, a pleiotrope agent able to both inhibit AChE and MAO-B, with potential interest against Alzheimer’s disease
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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 μM) and (h)MAO-B (IC50 = 6.4 μM).
- Guieu, Benjamin,Lecoutey, Cedric,Legay, Rémi,Davis, Audrey,De Oliveira Santos, Jana Sopkova,Altomare, Cosimo Damiano,Catto, Marco,Rochais, Christophe,Dallemagne, Patrick
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- ISOINDOLE DERIVATIVE
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Disclosed is a compound of formula (I) and a stereoisomer thereof: wherein R1, R2, R3 and R4 are as defined in the present disclosure.
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Paragraph 0228; 0234
(2021/02/25)
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- GLUCOSE METABOLISM MODULATING COMPOUNDS
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The present invention provides, inter alia, dihydropyridone compounds and compositions, including analogs of a vesicular monoamine transporter type 2 (VMAT2) antagonist. The present invention also provides methods of using such compounds/analogs for modulating glucose levels, and/or preventing, treating, or ameliorating the effects of diabetes and hyperglycemia.
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Sheet sheet 12 of 13
(2016/11/14)
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- Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents
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Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvβ3, αvβ5, αvβ6, and αvβ8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvβ3 and αvβ5.
- Adams, James,Anderson, Edward C.,Blackham, Emma E.,Chiu, Yin Wa Ryan,Clarke, Thomas,Eccles, Natasha,Gill, Luke A.,Haye, Joshua J.,Haywood, Harvey T.,Hoenig, Christian R.,Kausas, Marius,Le, Joelle,Russell, Hannah L.,Smedley, Christopher,Tipping, William J.,Tongue, Tom,Wood, Charlotte C.,Yeung, Jason,Rowedder, James E.,Fray, M. Jonathan,McInally, Thomas,Macdonald, Simon J. F.
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supporting information
p. 1207 - 1212
(2015/04/27)
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- Facile synthesis of N-(9-fluorenylmethyloxycarbonyl)-3-amino-3-(4,5- dimethoxy-2-nitrophenyl)propionic acid as a photocleavable linker for solid-phase peptide synthesis
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A photocleavable linker, N-(9-fluorenylmethyloxycarbonyl)-3-amino-3-(4,5- dimethoxy-2-nitrophenyl)propionic acid was synthesized from veratraldehyde, with simple reaction and separation steps. This linker was stable under the normal solid-phase peptide sy
- Kim, Jaehi,Kyeong, San,Shin, Dong-Sik,Yeo, Sewon,Yim, Joonhyuk,Lee, Yoon-Sik
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p. 733 - 736
(2013/05/09)
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- Kinetic resolution of aromatic β-amino acids by ω-transaminase
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Racemic aromatic β-amino acids have been kinetically resolved into (R)-β-amino acids with high enantiomeric excess (>99%) by a novel ω-TA with ca. 50% conversion.
- Bea, Han-Seop,Park, Hye-Jeong,Lee, Sang-Hyeup,Yun, Hyungdon
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supporting information; experimental part
p. 5894 - 5896
(2011/06/23)
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- HYPOGLYCEMIC DIHYDROPYRIDONES
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The present invention provides, inter alia, a compound of formula I: wherein the substituent designations are indicated in the Specification. The present invention also provides pharmaceutical compositions comprising a compound of formula I, and methods o
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Page/Page column 57
(2010/04/03)
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- An efficient new enzymatic method for the preparation of β-aryl-β-amino acid enantiomers
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An efficient synthesis of β-aryl-β-amino acid enantiomers has been developed via the lipase-catalysed enantioselective hydrolysis of the corresponding racemic ethyl esters in an organic solvent. High enantioselectivities (E >100) were observed when the lipase PS-catalysed reactions were performed with H2O (0.5 equiv) in diisopropyl ether at 45 °C. The products could be easily separated and were obtained in good yields of ≥40%.
- Tasnadi, Gabor,Forro, Eniko,Fueloep, Ferenc
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p. 2072 - 2077
(2008/12/22)
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- Novel hypoglycemic dihydropyridones serendipitously discovered from O- versus C-alkylation in the synthesis of VMAT2 antagonists
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Vesicular monoamine transporter type 2 (VMAT2) is a newly emerging target for both diagnostic and therapeutic applications in diabetes mellitus. In pursuit of novel VMAT2 antagonists, we identified a potent hypoglycemic agent with a novel dihydropyridone
- Xie, Yuli,Raffo, Anthony,Ichise, Masanori,Deng, Shixian,Harris, Paul E.,Landry, Donald W.
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scheme or table
p. 5111 - 5114
(2009/07/18)
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- Competitive formation of β-amino acids, propenoic, and ylidenemalonic acids by the Rodionov reaction from malonic acid, aldehydes, and ammonium acetate in alcoholic medium
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The Rodionov reaction of 49 available aliphatic and aromatic aldehydes with malonic acid and ammonium acetate in alcoholic medium, resulting in formation of β-amino acids, propenoic, and ylidenemalonic acids, was studied. Certain regioselectivity regularities of the reaction were revealed. Among the variety of ketones studied, cyclohexanone is the only whose reaction yields a β-amino acid. Unusual dehydrofluorination of 6-chloro-2-fluorocinnamic acid under the Rodionov reaction was discovered. 2005 Pleiades Publishing, Inc.
- Lebedev,Lebedeva,Sheludyakov,Kovaleva,Ustinova,Kozhevnikov
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p. 1113 - 1124
(2007/10/03)
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- METHODS OF USING AND COMPOSITIONS COMPRISING (+)-3-(3,4-DIMETHOXY-PHENYL)-3-(1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PROPIONAMIDE
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Enantiomerically pure (+)-3 -(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide, and prodrugs, metabolites, polymorphs, salts, solvates (e.g., hydrates), and clathrates thereof are discussed. Methods of treating and/or preventing vari
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Page/Page column 31-32; 38
(2008/06/13)
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- Aromatic β-amino acids as Asp-Phg mimics in LDV derived VLA-4 antagonists
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Aromatic β-amino acid esters 2a-h were prepared in racemic and enantiomerically pure form by the Radionow reaction or based on the method described by Davis and used as mimics of the Asp-Phg C-terminus in LDV derived VLA-4 antagonists. As a promising β-am
- Wehner, Volkmar,Blum, Horst,Kurz, Michael,Stilz, Hans Ulrich
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p. 2023 - 2036
(2007/10/03)
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- Immunotherapeutic imides/amides
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Imide/amide ethers and alcohols are inhibitors of cytokines including tumor necrosis factor α and can be used to combat cachexia, endotoxic shock, arthritis, asthma, and retrovirus replication. A typical embodiment is 3-Phthalimido-3-(3', 4'-dimethoxyphenyl)propan-1-ol.
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- Cyclic amides
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Cyclic amides are inhibitors of tumor necrosis factor and can be used to combat cachexia, endotoxic shock, and retrovirus replication. A typical embodiment is 3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide.
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- One-Pot Cyclization of Alkoxy-3-Aminoindan-1-ones.
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3-Amino-3-alkoxyphenylpropionic acids, prepared from alkoxybenzaldehydes, are cyclized in one step into 3-aminoindan-1-ones using trifluoroacetic acid and trifluoroacetic anhydride. Key Words: One-pot cyclization; Aminoindanones; Electrodonating substitue
- Dallemagne, Patrick,Rault, Sylvain,Pilo, Juan Carlos,Foloppe, Marie Paule,Robba, Max
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p. 6327 - 6328
(2007/10/02)
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- Substituted aryl ureas as high potency sweeteners
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Substituted ureas and thioureas are disclosed for use as high potency sweeteners.
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