- GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes
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GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp-43 with an IC50 value of 0.63 μM by a structure-activity relationship (SAR) study. Further studies showed that Comp-43 reduces mHTT levels by targeting GPR52 and promotes survival of mouse primary striatal neurons. Moreover, in vivo study showed that Comp-43 not only reduces mHTT levels but also rescues HD-related phenotypes in HdhQ140 mice. Taken together, our study confirms that inhibition of GPR52 is a promising strategy for HD therapy, and the GPR52 antagonist Comp-43 might serve as a lead compound for further investigation.
- Wang, Congcong,Zhang, Yu-Fang,Guo, Shimeng,Zhao, Quan,Zeng, Yanping,Xie, Zhicheng,Xie, Xin,Lu, Boxun,Hu, Youhong
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p. 941 - 957
(2020/11/30)
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- Straightforward synthesis of functionalized (E)-3-acylacrylic acids
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An experimentally simple, mild and straightforward synthetic route towards diversely functionalized (E)-3-acylacrylic acids is described, with Horner-Wadsworth-Emmons (HWE) reaction as the key step. The substrate scope and limitations of the HWE reaction were investigated with a range of β-ketophosphonates. Glyoxylic acid monohydrate was demonstrated to be fully compatible with the HWE reaction conditions, thus avoiding a troublesome hydrolysis of the corresponding 3-acylacrylates in the last step and providing a valuable synthetic shortcut.
- Sivák, Ivan,Václav, Jakub,Berke?, Du?an,Kolarovi?, Andrej
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p. 8871 - 8875
(2015/11/02)
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- Diastereo- and enantioselective asymmetric hydrogenation of α-amido-β-keto phosphonates via dynamic kinetic resolution
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Dynamic kinetic resolution of various α-amido-β-keto phosphonates via asymmetric hydrogenation proceeded efficiently to give the corresponding β-hydroxy-α-amido phosphonates in high diastereo- and enantioselectivities (up to 99:1 syn/anti, 99.8% ee). The addition of catalytic amounts of CeCl3 3 7H2O is necessary to achieve both good selectivity and catalytic efficiency under mild reaction conditions.
- Tao, Xiaoming,Li, Wanfang,Li, Xiaoming,Xie, Xiaomin,Zhang, Zhaoguo
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supporting information
p. 72 - 75
(2013/03/28)
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- Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity
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A series of γ-lactam prostaglandin E1 analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (Ki values: mEP2 = 9.3 nM, mEP4 = 0.41 nM). A structure-activity relationship study is presented.
- Kambe, Tohru,Maruyama, Toru,Nakano, Masayuki,Nakai, Yoshihiko,Yoshida, Tadahiro,Matsunaga, Naoki,Oida, Hiroji,Konaka, Akira,Maruyama, Takayuki,Nakai, Hisao,Toda, Masaaki
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scheme or table
p. 396 - 401
(2012/02/16)
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- Highly enantioselective epoxidation of α,β-unsaturated ketones catalyzed by primary-secondary diamines
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The asymmetric epoxidation of α,β-unsaturated ketones has been achieved by using functional and readily accessible primary-secondary diamines as the catalysts, giving the useful alkyl epoxy products with good yields and high enantioselectivities (up to 99% ee). Copyright
- Lu, Yingpeng,Zheng, Changwu,Yang, Yingquan,Zhao, Gang,Zou, Gang
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supporting information; experimental part
p. 3129 - 3133
(2012/01/03)
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- Synthesis of pyrimidine-containing nucleoside β-(R/S)- hydroxyphosphonate analogues
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A concise route to nucleoside β-hydroxyphosphonate analogues is described. The use of a nucleoside β-ketophosphonate as the key intermediate allowed both the (R) and (S) isomers of β-hydroxyphosphonate analogues in the pyrimidine series to be accessed. Such derivatives may be considered as stable mimics of 5′-monophosphate nucleosides and, therefore, could be the starting point for the development of potential therapeutic agents. Copyright
- Meurillon, Maia,Chaloin, Laurent,Perigaud, Christian,Peyrottes, Suzanne
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supporting information; experimental part
p. 3794 - 3802
(2011/09/30)
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- Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization.
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A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the la
- Elworthy, Todd R,Kertesz, Denis J,Kim, Woongki,Roepel, Michael G,Quattrocchio-Setti, Lina,Smith, David B,Tracy, Jahari Laurant,Chow, Audrey,Li, Fujun,Brill, Emma R,Lach, Leang K,McGee, Daren,Yang, Diana S,Chiou, San-San
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p. 1655 - 1659
(2007/10/03)
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- GAMMA LACTAMS AS PROSTAGLANDIN AGONISTS AND USE THEREOF
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1,2-substituted 5-pyrrolidinone compounds are provided, and methods of treatment and pharmaceutical composition that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including treating or preventing preterm labor, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteporosis and other destructive bone disease or disorder, renal dysfunction, an immune deficiency disorder, dry eye, ichthyosis, elevated intraocular pressure, sleep disorder, or gastric ulcer, inflammatory disorders and other diseases and disorders associated with the prostaglandin family of compounds.
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- Synthetic approaches to C-glucosinolates
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In these pages, short and efficient synthetic approaches to C-analogs of glucosinolates are described. Starting from D-glucose, C-glucotropaeolin (6) and C-glucocapparin (11) were synthesized in three steps. Preliminary enzymatic assays involving sulfatase and myrosinase have been performed. (C) 2000 Published by Elsevier Science Ltd.
- Aucagne, Vincent,Gueyrard, David,Tatibou?t, Arnaud,Quinsac, Alain,Rollin, Patrick
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p. 2647 - 2654
(2007/10/03)
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- The Chemistry of 2H-3,1-Benzoxazine-2,4(1H)-dione (Isatoic Anhydride). 20. Synthesis and Wittig Reactions of Dimethyl (4-Oxo-1,4-dihydro-Quinolin-2-yl)methanephosphonates
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Isatoic anhydrides react with dilithiated 2-oxoalkanephosphonates to give dimethyl (4-oxo-1,4-dihydroquinolin-2-yl)methanephosphonates 5.These phosphonates undergo a Horner reaction with aldehydes to produce 2-(1-alkenyl)-4(1H)-quinolinones 10 in good yie
- Coppola, Gary M.
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- 9-Substituted carbacyclin analogs
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Novel compounds of the following formula: STR1
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- 9-Substituted carbacyclin analogs
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Novel compounds of the following general formula: STR1
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- 9-Substituted carbacyclin analogs
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Novel compounds of the following general formula: STR1
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- 11-Desoxy-15-substituted-ω-pentanor prostaglandins
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11-DESOXY-15-SUBSTITUTED-ω-PENTANORPROSTAGLANDINS AND VARIOUS INTERMEDIATES EMPLOYED IN THEIR PREPARATION. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins, but exhibit a greater
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- Cyclopentanone derivatives
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Cyclopentane derivatives of the formula: STR1 wherein R1 represents hydrogen or a carboxylic acyl group, and either (I) R2 represents a group of the formula: (wherein R3 and R4 represent hydrogen or alkyl, and R5 represents hydrogen, or alkyl, alkoxy, cycloalkyl or adamantyl, or R5 represents alkyl substituted by alkoxy, or by cycloalkyl or by adamantyl, or the group --CR3 R4 R5 together forms a cycloalkyl or adamantyl group), X represents trans-vinylene or ethylene and Y represents carbonyl or a group of the formula: STR2 wherein R6 represents hydrogen or alkyl, and R7 represents hydrogen or a carboxylic acyl group, or else (ii) R2 represents a group of the formula: (wherein A represents alkylene, Z represents a direct bond or oxygen or sulphur, and R8 represents an aryl or heterocyclyl group which may be substituted by one or more of halogen, alkyl, alkoxy and trihalomethyl), X in formula I represents ethylene or trans-vinylene and Y in formula I represents carbonyl or a group of formula III, or else (iii) R2 represents a group R8 and X and Y in formula I represent simultaneously ethylene and carbonyl, trans-vinylene and carbonyl, or ethylene and --CH(OR7)-- groups respectively. The compounds are new and possess pharmacological properties similar to those of prostaglandins.
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- 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins of the two series
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The 15-substituted-ω-pentanorprostaglandins and various intermediates employed in their preparation. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins, but exhibit a greater tissue specificity of action.
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- Magnesium salts of 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-omega-pentanoprostaglandins
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The magnesium salts of 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-ω-pentanorprostaglandins are disclosed. The novel prostaglandin salt of this invention have been found to have activity profiles comparable to the parent prostaglandins, but ex
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- Phenyl-substituted prostaglandin-e type analogs
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This invention is a group of phenyl-substituted PGE-type, PGF-type, PGA-type and PGB-type compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.
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- Bone deposition by 16-aryl-13,14-dihydro-PGE2 p-biphenyl esters
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Bone deposition in animals is produced by the administration of a 16-aryl-13,14-dihydro-PGE2 p-biphenyl ester.
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- 15-Substituted-ω-pentanorprostaglandins
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The 15-substituted-ω-pentanorprostaglandins and various intermediates employed in their preparation. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins, but exhibit a greater tissue specificity of action.
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- P-biphenyl esters of 15-substituted-ω-pentanorprostaglandins
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The p-biphenyl esters of 15-substituted-ω-pentanorprostaglandins are disclosed. The novel prostaglandin esters of the invention exhibit the biological properties of corresponding prostaglandins from which they are derived, but have reduced side effects, and are further valuable because they are easily crystallized and thus may be simply isolated and purified and compounded into medicaments.
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- 2-Descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-ω-pentanorprostaglandins
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The 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-ω-pentanorprostaglandins and various intermediates employed in their preparation. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins, but exhibit a greater tissue specificity of action.
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