- A benzo[b]thiophene-based selective type 4 S1P receptor agonist
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S1P receptors (S1PR1-5) are a group of GPCRs activated by a high affinity binding with S1P that have important roles in the regulation of the immune system. A potent S1PR agonist FTY720 is an immunomodulator used to treat multiple sclerosis and several ‘second generation’ drugs are under clinical development. Subtype-selective agonists have been reported for each S1PR isotype, some of which are used as pharmacological tools for functional studies. Here we report the discovery and initial characterization of compound 5c, a benzo[b]thiophene amino carboxylate which exhibits potent and selective agonist activity for S1PR4. Compound 5c has an EC50= 200 nM as an agonist in GTPγ35S binding assay for S1PR4 and exhibits no activity against S1PR1,2,3,5. We confirmed its potent activity and decent S1PR subtype selectivity using biochemical and cellular assays.
- Hur, Wooyoung,Rosen, Hugh,Gray, Nathanael S.
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Read Online
- Latent Nucleophilic Carbenes
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Using DFT and ab initio calculations, we demonstrate that noncyclic formamidines can undergo thermal rearrangement into their isomeric aminocarbenes under rather mild conditions. We synthesized the silylformamidine, for which the lowest activation energy in this process was predicted. Experimental studies proved it to serve as a very reactive nucleophilic carbene. The reactions with acetylenes, benzenes, and trifluoromethane proceeded via insertion into sp, sp2, and spCH bonds. The carbene also reacted with the functional groups, such as CHO, COR, and CN at double or triple bonds, displaying high mobility of the trimethylsilyl group. The obtained silylformamidine can be considered as a latent nucleophilic carbene. It can be prepared in bulk quantities, stored, and used when the need arises. Calculation results predict similar behavior for some other silylated formamidines and related compounds.
- Marchenko, Anatoliy,Koidan, Georgyi,Hurieva, Anastasiya,Shvydenko, Kostiantyn,Rozhenko, Alexander B.,Rusanov, Eduard B.,Kyrylchuk, Andrii A.,Kostyuk, Aleksandr
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p. 373 - 385
(2021/12/27)
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- Palladium-Catalyzed, Norbornene-Mediated, ortho-Amination ipso-Amidation: Sequential C-N Bond Formation
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A palladium-catalyzed, norbornene-mediated ortho- and ipso-C-N bond-forming Catellani reaction is reported. This reaction proceeds through a sequential intermolecular amination followed by intramolecular cyclization of a tethered amide. The products, ortho-aminated dihydroquinolinones, were generated in moderate to good yields and are present in bioactive molecules. This work highlights the challenge of competing intra- vs intermolecular palladium-catalyzed processes.
- Whyte, Andrew,Olson, Maxwell E.,Lautens, Mark
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supporting information
p. 345 - 348
(2018/01/27)
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- F- Nucleophilic-Addition-Induced [3 + 2] Annulation: Direct Access to CF3-Substituted Indenes
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An efficient [3 + 2] annulation of (2,2-difluorovinyl)-2-iodoarenes and internal alkynes was developed for the synthesis of 1-(trifluoromethyl)-1H-indenes. The success of this strategy hinges upon a well-balanced process for the generation of two transient reactive species, specifically trifluoroethylsilver and alkenylpalladium intermediates, in the same molecule, as well as a smooth transmetalation step, which delicately joins together these two different metallic intermediates.
- Tang, Hai-Jun,Zhang, Yu-Feng,Jiang, Yi-Wen,Feng, Chao
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supporting information
p. 5190 - 5193
(2018/09/12)
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- Synthesis of Functionalized Alkylidene Indanes and Indanones through Tandem Phosphine-Palladium Catalysis
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Densely functionalized alkylidene indanes and indanones can be prepared efficiently in one pot, in high yields with good stereoselectivities (in some cases exclusively the Z-isomer), through a route involving phosphine-catalyzed Michael addition followed
- Fan, Yi Chiao,Kwon, Ohyun
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supporting information
p. 2058 - 2061
(2015/05/20)
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- IMIDAZOPYRIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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The invention provides compounds of Formulas Ia-Ib, stereoisomers or pharmaceutically acceptable salts thereof, wherein A, X, Ra, R1, R2, R4, R5 and R16 are defined herein, a pharmaceutical
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Paragraph 0277
(2014/08/06)
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- IMIDAZOPYRIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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The invention provides TYK2 inhibitors of Formulas (la-lb), stereoisomers or pharmaceutically acceptable salts thereof, wherein A, X, Ra, R1, R2, R4, R5 and R16 are defined herein, a pharma
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Page/Page column 55; 56
(2013/04/10)
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- Convergent synthesis of (-)-quinocarcin based on the combination of sonogashira coupling and gold(I)-catalyzed 6-endo-dig hydroamination
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The total synthesis of the pentacyclic tetrahydroisoquinoline alkaloid quinocarcin, which possesses intriguing structural and biological features, has been achieved through a gold(I)-catalyzed regioselective hydroamination reaction. It is noteworthy that the regioselectivity of the intramolecular hydroamination of an unsymmetrical alkyne could be completely switched through substrate control. Other key features of this synthesis include the highly stereoselective synthesis of 2,5-cis-pyrrolidine through the intramolecular amination of the bromoallene and the Lewis acid mediated ring opening of dihydrobenzofuran. Golden(I): A convergent asymmetric total synthesis of quinocarcin employed Sonogashira and Au-catalyzed hydroamination reactions (see scheme). The regioselectivity of the intramolecular hydroamination of an unsymmetrical alkyne was switched by substrate control. Copyright
- Chiba, Hiroaki,Sakai, Yuki,Ohara, Ayako,Oishi, Shinya,Fujii, Nobutaka,Ohno, Hiroaki
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supporting information
p. 8875 - 8883
(2013/07/26)
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- Synthesis of indolines via a domino Cu-catalyzed amidation/cyclization reaction
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(Chemical Equation Presented) A highly efficient one-pot procedure for the synthesis of indolines and their homologues based on a domino Cu-catalyzed amidation/nucleophilic substitution reaction has been developed. Substituted 2-iodophenethyl mesylates and related compounds afforded the corresponding products in excellent yields. No erosion of optical purity was observed when transforming enantiomerically pure mesylates under the reaction conditions.
- Minatti, Ana,Buchwald, Stephen L.
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supporting information; experimental part
p. 2721 - 2724
(2009/05/27)
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- 4-Substituted (benzo[b]thiophene-2-carbonyl)guanidines as novel Na +/H+ exchanger isoform-1 (NHE-1) inhibitors
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A series of 4-substituted (benzo[b]thiophene-2-carbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardioprotective efficacy both in vitro and in vivo. Several analogs exhibited a strong inhibition on NHE-1, and which was generally well correlated with their cardioprotective efficacy. Especially the 4-nitro 20 and cyano 50 compounds excellently improved the cardiac function and reduced infarct size against ischemia/reperfusion injury.
- Lee, Sunkyung,Lee, Hyunsuk,Kyu, Yang Yi,Byung, Ho Lee,Yoo, Sung-Eun,Lee, Kyunghee,Nam, Sook Cho
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p. 2998 - 3001
(2007/10/03)
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- ISOQUINOLINE-3-CARBOXYLIC ACID AMIDES AND PHARMACEUTICAL USES THEREOF
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The present invention relates to novel isoquinoline-3-carboxylic acid amides having α7 nicotinic acetylcholine receptor agonistic activity, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
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- Compounds and method for inhibiting MRP1
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The present invention relates to a compound of formula (I), which is useful for inhibiting resistant neoplasms where the resistance is conferred in part or in total by MRP1.
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Page column 52
(2010/02/05)
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- Fused pyridine derivatives
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The present provides a condensed pyridine compound (I) represented by the following formula: (wherein, R2represents ring A represents benzene ring, pyridine ring, thiophene ring or furan ring; and B represents its pharmaceutically acceptable salt or hydrates thereof, which is a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating or preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
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- Fluorine as an ortho-directing group in aromatic metalation: A two step preparation of substituted benzo[b] thiophene-2-carboxylates
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A simple 2-step synthesis of B-ring substituted benzo[b]thiophene-2-carboxylates from aryl fluorides has been developed. The route involves a selective lithiation ortho to fluorine, followed by formylation, and subsequently, displacement of fluorine with
- Bridges, Alexander J.,Lee, Arthur,Maduakor, Emmanuel C.,Eric Schwartz
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p. 7499 - 7502
(2007/10/02)
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