- NOVEL LYSOPHOSPHATIDIC ACID DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a compound that specifically activates an LPA4 receptor, and a pharmaceutical composition containing the same. SOLUTION: This invention relates to a novel lysophosphatidic acid derivative that has an agonistic action on an LPA4 receptor and is useful for the prevention and/or treatment of a disease with angiodysplasia caused by the LPA4 receptor, or a disease associated with angiopathy, or symptoms associated therewith. This invention also relates to a pharmaceutical composition containing the lysophosphatidic acid derivative. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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- PD(II)-CATALYZED ENANTIOSELECTIVE C-H ARYLATION OF FREE CARBOXYLIC ACIDS
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The invention includes procedures for stereoselective β-arylation of carboxylic acids having a β-carbon atom. For example, stereoselective arylation procedures include the following reactions: (I)
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Page/Page column 29-30; 31; 33-34
(2019/11/12)
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- Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Free Carboxylic Acids
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A monoprotected aminoethyl amine chiral ligand based on an ethylenediamine backbone was developed to achieve Pd-catalyzed enantioselective C(sp3)-H arylation of cyclopropanecarboxylic and 2-aminoisobutyric acids without using exogenous directing groups. This new chiral catalyst affords new disconnection for preparing diverse chiral carboxylic acids from simple starting materials that are complementary to the various ring forming approaches.
- Shen, Peng-Xiang,Hu, Liang,Shao, Qian,Hong, Kai,Yu, Jin-Quan
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supporting information
p. 6545 - 6549
(2018/05/23)
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- Indazole-6-phenylcyclopropylcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy
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GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.
- McCoull, William,Bailey, Andrew,Barton, Peter,Birch, Alan M.,Brown, Alastair J. H.,Butler, Hayley S.,Boyd, Scott,Butlin, Roger J.,Chappell, Ben,Clarkson, Paul,Collins, Shelley,Davies, Robert M. D.,Ertan, Anne,Hammond, Clare D.,Holmes, Jane L.,Lenaghan, Carol,Midha, Anita,Morentin-Gutierrez, Pablo,Moore, Jane E.,Raubo, Piotr,Robb, Graeme
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p. 3187 - 3197
(2017/04/19)
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- Synthesis and in vitro evaluation of novel N-cycloalkylcarbamates as potential cholinesterase inhibitors
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Abstract: This present paper describes the preparation and characterization of a series of O-substituted N-cycloalkylcarbamate derivatives. These compounds were tested as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All studied carbamates exhibited moderate inhibitory activity of both cholinesterases with values of IC50 in the range of 36.1–78.6?μM for AChE and 9.8–215.4?μM for BChE, respectively. These values are comparable with those values of inhibition obtained with the established drug rivastigmine. The cytotoxicity of all carbamates was evaluated using standard in vitro test with Jurkat cells. Many of the studied carbamates can be considered as promising compounds for potential medicinal applications with regard to their inhibitory activity as well as negligible cytotoxicity.
- Horáková, Eva,Drabina, Pavel,Br??ková, Lenka,?těpánková, ?árka,Vor?áková, Katarína,Sedlák, Milo?
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p. 2143 - 2153
(2017/09/25)
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- Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1
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Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B. Several cyclopropylamine containing compounds were found to be highly potent and selective inhibitors of LSD1. A novel series cyclopropylimine compounds also exhibited strong inhibitory activity against LSD1.Structure activity relationships (SAR) of these compounds are discussed. Docking studies were performed to provide possible binding models of a representative compound in LSD1 and MAO-A. Moreover, these modeling studies can rationalize the observed SARs and selectivity.
- Zhou, Chao,Wu, Fangrui,Lu, Lianghao,Wei, Liping,Pai, Eric,Yao, Yuan,Song, Yongcheng
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- Oxidative ring-opening of ferrocenylcyclopropylamines to N-ferrocenylmethyl β-hydroxyamides
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The in situ reduction of ferrocenyl cyclopropylimines to the corresponding amines triggers a facile oxidative ring-opening to yield the formal four-electron oxidation products: N-ferrocenylmethyl β-hydroxyamides. This process is believed to proceed via generation of a ferrocinium ion in the presence of air, leading to facile formation of a distonic radical cation that is ultimately trapped by oxygen.
- Gee, Yi Sing,Goertz, Neils J. M.,Gardiner, Michael G.,Hyland, Christopher J. T.
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p. 2498 - 2503
(2016/03/01)
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- (HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS
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The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula I as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.
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- (HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS
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The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.
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- ARYLCYCLOPROPYLAMINE BASED DEMETHYLASE INHIBITORS OF LSD1 AND THEIR MEDICAL USE
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The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. Thus, in one specific aspect the invention relates to formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (IX).
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- PYRAZINE AND IMIDAZOLIDINE DERIVATIVES AND THEIR USES TO TREAT HEPATITIS C
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Disclosed herein are compounds useful for treating a viral infection, such HCV.
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Page/Page column 327
(2012/08/08)
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- Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors
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Asymmetric cyclopropanation of styrenes by tert-butyl diazoacetate followed by ester hydrolysis and Curtius rearrangement gave a series of tranylcypromine analogues as single enantiomers. The o,- m- and p-bromo analogues were all more active than tranylcypromine in a LSD1 enzyme assay. The m- and p-bromo analogues were micromolar growth inhibitors of the LNCaP prostate cancer cell line as were the corresponding biphenyl analogues prepared from the bromide by Suzuki crosscoupling.
- Benelkebir, Hanae,Hodgkinson, Christopher,Duriez, Patrick J.,Hayden, Annette L.,Bulleid, Rosemary A.,Crabb, Simon J.,Packham, Graham,Ganesan
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p. 3709 - 3716
(2011/08/02)
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- Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2
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LSD1 and LSD2 histone demethylases are implicated in a number of physiological and pathological processes, ranging from tumorigenesis to herpes virus infection. A comprehensive structural, biochemical, and cellular study is presented here to probe the potential of these enzymes for epigenetic therapies. This approach employs tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. This drug is a clinically validated antidepressant known to target monoamine oxidases A and B. These two flavoenzymes are structurally related to LSD1 and LSD2. Mechanistic and crystallographic studies of tranylcypromine inhibition reveal a lack of selectivity and differing covalent modifications of the FAD cofactor depending on the enantiomeric form. These findings are pharmacologically relevant, since tranylcypromine is currently administered as a racemic mixture. A large set of tranylcypromine analogues were synthesized and screened for inhibitory activities. We found that the common evolutionary origin of LSD and MAO enzymes, despite their unrelated functions and substrate specificities, is reflected in related ligand-binding properties. A few compounds with partial enzyme selectivity were identified. The biological activity of one of these new inhibitors was evaluated with a cellular model of acute promyelocytic leukemia chosen since its pathogenesis includes aberrant activities of several chromatin modifiers. Marked effects on cell differentiation and an unprecedented synergistic activity with antileukemia drugs were observed. These data demonstrate that these LSD1/2 inhibitors are of potential relevance for the treatment of promyelocytic leukemia and, more generally, as tools to alter chromatin state with promise of a block of tumor progression.
- Binda, Claudia,Valente, Sergio,Romanenghi, Mauro,Pilotto, Simona,Cirilli, Roberto,Karytinos, Aristotele,Ciossani, Giuseppe,Botrugno, Oronza A.,Forneris, Federico,Tardugno, Maria,Edmondson, Dale E.,Minucci, Saverio,Mattevi, Andrea,Mai, Antonello
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supporting information; experimental part
p. 6827 - 6833
(2010/07/03)
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- CYCLOPROPYL AMINE DERIVATIVES
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Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compoun
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Page/Page column 84-85
(2008/06/13)
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- 5-HT2C RECEPTOR AGONISTS AS ANORECTIC AGENTS
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This invention relates to compounds which modulate receptors of the 5-HT2 family of receptors, and particularly to compounds which modulate 5-HT2C receptors. Compounds of the invention include agonists and selective agonists for the 5-HT2C receptor. Compounds of the invention include selective agonists for the 5-HT2C receptor which exhibit significantly less or no agonist activity on the 5-HT2A receptor and/or the 5-HT2B receptor. Compounds of this invention are those of Formula I and pharmaceutically acceptable salts, esters and solvates (including hydrates) wherein variables are defined in the specification hereof.
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Page/Page column 82
(2008/06/13)
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- COMPOUNDS WHICH POTENTIATE GLUTAMATE RECEPTOR AND USES THEREOF IN MEDICINE
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This invention relates to potentiation of the glutamate receptor by novel compounds of formula (I): The invention also relates to the use of the derivatives in treating diseases and conditions mediated by potentiation of the glutamate receptor, compositio
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Page/Page column 37-38
(2008/06/13)
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- CATHEPSIN CYSTEINE PROTEASE INHIBITORS
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This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
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Page/Page column 48-49
(2010/02/12)
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- 4-OXO-1-(3-SUBSTITUTED PHENYL-1,4-DIHYDRO-1,8-NAPHTHYRIDINE-3-CARBOXAMIDE PHOSPHODIESTERASE-4 INHIBITORS
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Compounds represented by Formula (I):or a pharmaceutically acceptable salt thereof, are phosphodiesterase 4 inhibitors useful in the treatment of asthma and inflammation and useful for the enhancement of cognition.
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- A novel route to cyclopropyl ketones, aldehydes, and carboxylic acids
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Cyclopropanation of α,β-unsaturated N-methoxy-N-methyl amides provided the cyclopropyl amides in far superior yields to those obtained with the corresponding ketones. The desired ketones are then readily accessible by the addition of organometallic reagents. Access to a variety functional groups, including aldehydes and carboxylic acids, is also described.
- Rodriques, Karen E.
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p. 1275 - 1278
(2007/10/02)
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