- MALIC ENZYME INHIBITORS
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The present invention relates to novel compounds useful as malic enzyme (ME) inhibitors, processes for their preparation and use of these compounds for the therapeutic treatment of disorders mediated by ME such as cancers (e.g. pancreatic ductal adenocarcinoma (PDAC)) in humans.
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- NEGATIVE ALLOSTERIC MODULATION OF GLUN3-CONTAINING N-METHYL-D-ASPARTATE RECEPTORS
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Disclosed are negative allosteric modulators of GluN3-containing NMDA receptors. In general, these compounds are highly selective for GluN3 (such as GluN3A and/or GluN3B) over GluN1 and/or GluN2. They can function as non-competitive antagonists with activity that is independent of membrane potential, glycine concentration, and extracellular pH. Also disclosed are pharmaceutical formulations of the negative allosteric modulators. These compounds can be used to enhance synaptic function and/or treating a neurological condition or disorder. Exemplary neurological conditions or disorders include, but are not limited to, major mental disorders, conditions that involve basal ganglia or altered dopamine, substance abuse/addiction or predisposition to substance abuse/addiction, pain disorders, developmental delay or situations with impaired learning, memory, and/or cognition, acute neuronal or glial injuries, and circuit disorders.
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Page/Page column 65
(2021/08/06)
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- Manganese/bipyridine-catalyzed non-directed C(sp3)–H bromination using NBS and TMSN3
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A Mn(II)/bipyridine-catalyzed bromination reaction of unactivated aliphatic C(sp3)?H bonds has been developed using N-bromosuccinimide (NBS) as the brominating reagent. The reaction proceeded in moderate-to-good yield, even on a gram scale. The introduced bromine atom can be converted into fluorine and allyl groups.
- Sneh, Kumar,Torigoe, Takeru,Kuninobu, Yoichiro
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supporting information
p. 885 - 890
(2021/05/05)
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- Bromination of α-Diazo Phenylacetate Derivatives Using Cobalt(II) Bromide
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A method for the bromination of α-diazo phenylacetate derivatives using cobalt(II) bromide is described. This bromination reaction features a short reaction time, broad substrate scope, operational simplicity, acid-free conditions, and gram-scalability. (Figure presented.).
- Wang, Haifeng,Sun, Xiangli,Hu, Manman,Zhang, Xiaoyi,Xie, Lele,Gu, Shuangxi
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supporting information
p. 3347 - 3351
(2020/07/04)
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- Activating ATRP Initiators to Incorporate End-Group Modularity into Photo-RAFT Polymerization
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Heterogeneous photocatalysis is increasingly used in reversible deactivation radical polymerization (RDRP). In this study, we found that alkyl bromide redox chemistry typically found in atom transfer radical polymerization (ATRP) can be incorporated in concert with dithiocarbonyl disulfide chemistry into the reversible addition-fragmentation chain transfer (RAFT) process via bismuth oxide photocatalysis. This amalgamation of mechanisms introduces end-group modularity - a new layer of control - into RAFT polymers uniquely enabled by photoredox catalysis. We found that a diversity of functionality can be installed at the α-end group via alkyl bromides, while the molecular weight distribution can be tuned seamlessly at the ω-end group through the simultaneous addition of multiple disulfides.
- Hakobyan, Karen,McErlean, Christopher S. P.,Müllner, Markus
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p. 10357 - 10365
(2020/12/23)
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- Visible Light-Mediated Conversion of Alcohols to Bromides by a Benzothiadiazole-Containing Organic Photocatalyst
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The search for metal-free, stable and high effective photocatalysts with sufficient photo-redox potentials remains a key challenge for organic chemists. Here, we present a benzothiadiazole-containing molecular organic photocatalyst with redox potentials of ?1.30 V and +1.64 V vs. SCE. The singlet state lifetime is 13 ns. Direct conversion from aliphatic alcohols to bromides has been conducted with the designed organic photocatalyst under visible light irradiation with high efficiency and selectivity. The catalytic efficiency of the novel benzothiadiazole-based photocatalyst is comparable with the state-of-art metal and non-metal catalysts. Furthermore, advanced photophysical studies including time-resolved photoluminescence and transient absorption spectroscopy offer a powerful support for photo-induced electron transfer from photocatalyst to the reactive substrates. Lastly, no photo-bleaching effect is observed, demonstrating the high stability and recyclable of the designed organic photocatalyst. (Figure presented.).
- Li, Run,Gehrig, Dominik W.,Ramanan, Charusheela,Blom, Paul W. M.,Kohl, Fabien F.,Wagner, Manfred,Landfester, Katharina,Zhang, Kai A. I.
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p. 3852 - 3859
(2019/07/15)
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- Synthesis and biological evaluation of 3-functionalized 2-phenyl- and 2-alkylbenzo[b]furans as antiproliferative agents against human melanoma cell line
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The key function of microtubules and mitotic spindle in cell division make them attractive targets in anticancer therapy. In the present study, functionalized in 3 position 2-phenyl- and 2-alkylbenzo[b]furans were synthesized and evaluated as antitumor ag
- Kwiecień, Halina,Peru?yńska, Magdalena,Stachowicz, Karolina,Piotrowska, Katarzyna,Bujak, Joanna,Kopytko, Patrycja,Dro?dzik, Marek
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supporting information
(2019/04/29)
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- New 4-aryl-1,3,2-oxathiazolylium-5-olates: Chemical synthesis and photochemical stability of a novel series of S-nitrosothiols
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S-nitrosothiols (RSNOs) remain one of the most popular classes of NO-donating compounds due to their ability to release nitric oxide (NO) under non-enzymatic means whilst producing an inert disulphide by-product. However, alligning these compounds to the different biological fields of NO research has proved to be problematic due to the inherent instability of such compounds under a variety of conditions including heat, light and the presence of copper ions. 1,3,2-Oxathiazolylium-5-olates (OZOs) represent an interesting subclass of S-nitrosothiols that lock the –SNO moiety into a five membered heterocyclic ring in an attempt to improve the compound's overall stability. The synthesis of a novel series of halogen-containing OZOs was comprehensively studied resulting in a seven-step route and overall yields ranging between 21 and 37%. The photochemical stability of these compounds was assessed to determine if S-nitrosothiols locked within these mesoionic ring systems can offer greater stability and thereby release NO in a more controllable fashion than their non-cyclic counterparts.
- Eilertsen, Monica,Allin, Steve M.,Pearson, Russell J.
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supporting information
p. 1106 - 1110
(2018/02/28)
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- Mandelic acid derived ionic liquids: synthesis, toxicity and biodegradability
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A series of ten ionic liquids (ILs) was synthesised from the renewable resource mandelic acid. The ILs showed low antimicrobial activity towards the thirteen bacterial and twelve fungal strains they were screened against. A general trend of increasing bacterial toxicity in the order methyl ester 60% in 28 days), a series of biodegradation transformation products has been proposed based on the degradation of the ester/amide alkyl chain. This data has allowed for an assessment of the effect of IL structural features on toxicity and biodegradation, particularly allowing for a comparison to earlier work where additional oxygen atoms were present to facilitate biodegradation and attenuate toxicity. The mandelic acid derived ILs did not pass the Closed Bottle test (OECD 301D) and can be included in the rules of thumb for the design of biodegradable ILs.
- Prydderch, Hannah,Haiβ, Annette,Spulak, Marcel,Quilty, Brid,Kümmerer, Klaus,Heise, Andreas,Gathergood, Nicholas
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p. 2115 - 2126
(2017/01/22)
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- Synthesis and PGE2 production inhibition of s-triazine derivatives as a novel scaffold in RAW 264.7 macrophage cells
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We present the synthesis and biological evaluation of a collection of s-triazine derivatives as a novel scaffold of compounds with the capability to inhibit the PGE2 production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE2 reduction at 10 μM concentration. Two compounds (7b and 7i) exhibiting >90% inhibition of PGE2 production were found to have IC50 values of 5.76 and 5.52 μM, respectively. They were counter screened for inhibition on COX-2 activity in a cell free assay. Specifically, compound 7i (R1 = 4-Bn-Ph, R2 = Cl, R3 = Ph, R5 = CO2Me) was highly active in cells while maintaining little COX-2 inhibition (~0% at 10 μM). Molecular docking study provides the possibility that compound 7i could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 instead of COX-2 enzyme. Based on this result, our synthetic efforts will focus on intensive structure-activity relationship (SAR) study of s-triazine scaffold to discovery a potential PGE2 synthesis inhibitor.
- Kang, Seoung Mook,Lee, Jinsung,Jin, Jae Ho,Kim, Minju,Lee, Sunhoe,Lee, Hwi Ho,Shin, Ji-Sun,Lee, Kyung-Tae,Lee, Jae Yeol
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p. 5418 - 5422
(2015/01/08)
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- Enantioselective construction of tetrasubstituted stereogenic carbons through bronsted base catalyzed michael reactions: α′-hydroxy enones as key enoate equivalent
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Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C-C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Bronsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.
- Badiola, Eider,Fiser, Bla,Gmez-Bengoa, Enrique,Mielgo, Antonia,Olaizola, Iurre,Urruzuno, Iaki,Garca, Jess M.,Odriozola, Jos M.,Razkin, Jess,Oiarbide, Mikel,Palomo, Claudio
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p. 17869 - 17881
(2015/02/19)
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- Conventional and microwave-assisted synthesis of 1,5-diaryl-2- thiohydantoins
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A simple and efficient method for synthesis of new 1,5-diaryl- 2-thiohydantoins using microwave radiation has been standardized. The compounds have been synthesized from phenylacetic acid by esterification, bromination, amination and cyclization using con
- Baile,Mahajan
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experimental part
p. 891 - 894
(2012/08/27)
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- Direct and selective benzylic oxidation of alkylarenes via C-H abstraction using alkali metal bromides
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A direct benzylic oxidation of alkylarenes via C-H bond abstraction was developed using alkali metal bromides and oxidants under mild conditions. This reaction proceeded with excellent selectivity by thermal oxidation or photooxidation to provide a broad range of carbonyl compounds containing electron-deficient aryl carbonyl compounds in high yields.
- Moriyama, Katsuhiko,Takemura, Misato,Togo, Hideo
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supporting information; experimental part
p. 2414 - 2417
(2012/06/18)
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- Acetamide compounds as glucokinase activators, their process and medicinal applications
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Acetamide derivatives, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or m
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Page/Page column 26
(2012/02/04)
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- A formal method for the de-N,N-dialkylation of Sommelet-Hauser rearrangement products
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Selective amine de-alkylation enables the conversion of Sommelet-Hauser rearrangement products into 2-aryl-2-bromoacetic acid derivatives. These compounds are valuable synthetic intermediates in the synthesis of α-aryl-α-amino or α-aryl-β-amino acid deriv
- Tayama, Eiji,Sato, Ryota,Takedachi, Keisuke,Iwamoto, Hajime,Hasegawa, Eietsu
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experimental part
p. 4710 - 4718
(2012/07/28)
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- Visible-light-mediated conversion of alcohols to halides
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The development of new means of activating molecules and bonds for chemical reactions is a fundamental objective for chemists. In this regard, visible-light photoredox catalysis has emerged as a powerful technique for chemoselective activation of chemical bonds under mild reaction conditions. Here, we report a visible-light-mediated photocatalytic alcohol activation, which we use to convert alcohols to the corresponding bromides and iodides in good yields, with exceptional functional group tolerance. In this fundamentally useful reaction, the design and operation of the process is simple, the reaction is highly efficient, and the formation of stoichiometric waste products is minimized.
- Dai, Chunhui,Narayanam, Jagan M.R.,Stephenson, Corey R.J.
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experimental part
p. 140 - 145
(2012/02/06)
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- Carbon-carbon bond-forming reactions of α-carbonyl carbocations: Exploration of a reversed-polarity equivalent of enolate chemistry
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Carbon-carbon bond-forming reactions of putative α-carbonyl carbocation intermediates generated by Lewis acid- or silver-promoted ionizations of toluenesulfonate or halide leaving groups are described. This under-exploited mode of reactivity represents an 'umpolung' of conventional enolate chemistry, and enables C-C bond construction in both intra- and intermolecular contexts. Attempts to develop diastereoselective variants of this process using chiral ester and oxazolidinone-based auxiliaries are discussed.
- Lai, Ping-Shan,Dubland, Joshua A.,Sarwar, Mohammed G.,Chudzinski, Michael G.,Taylor, Mark S.
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supporting information; experimental part
p. 7586 - 7592
(2011/10/12)
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- Ethynyl-1,2-benziodoxol-3(1H)-one (EBX): An exceptional reagent for the ethynylation of keto, cyano, and nitro esters
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Hot alkyne! The in situ generation of ethynyl-1,2-benziodoxol-3(1H)-one (EBX) from a silyl-protected reagent by using TBAF is reported. EBX displayed exceptional acetylene transfer ability onto stabilized enolates (see scheme), even at -78 □°C. The mild reaction conditions allowed the first ethynylation reactions of linear keto, cyano, and nitro esters in high yields to give all-carbon quaternary centers or non-natural amino acids after selective reduction of the nitro group.
- Gonzalez, Davinia Fernandez,Brand, Jonathan P.,Waser, Jerome
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supporting information; experimental part
p. 9457 - 9461
(2010/10/03)
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- A NOVEL 4-METHYLBENZENESULPHONATE SALT AND A PROCESS FOR PREPARING A PHARMACEUTICAL COMPOSITION COMPRISING THE SALT
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The invention provides a 4-methylbenzenesulphonate salt of the muscarinic antagonist (R)- 1-(4-fluorophenethyl)-3-((S)-2-phenyl-2-(piperidin-1 -yl)propanoyloxy)-1- azoniabicyclo[2.2.2]octane and its use in therapy,as well as a process for preparing a pharmaceutical composition comprising the salt and its use in therapy.
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Page/Page column 26-27
(2010/12/29)
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- ACETAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS, THEIR PROCESS AND MEDICINAL APPLICATION
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Acetamide derivatives, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or m
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Page/Page column 20; 21
(2010/12/29)
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- Studies on the Eschenmoser coupling reaction and insights on its mechanism. Application in the synthesis of Norallosedamine and other alkaloids
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The conditions of the Eschenmoser coupling reaction were studied. The formation of the α-thioiminium ion was achieved faster in the presence of an additive (NaI) and dry chloroform as the preferred solvent. The developed conditions were used for the second part of the reaction (the sulfur extrusion itself). The present protocol avoids the formation of byproducts, which were previously described as a major drawback to be overcome. Electrospray ionization tandem mass spectrometry was used to characterize some aspects (intermediates) of the first step of the reaction mechanism. Some reduction conditions were properly tested and the selected conditions were applied to the synthesis of the natural alkaloid Norallosedamine and other derivatives.
- Neto, Brenno A.D.,Lapis, Alexandre A.M.,Bernd, Alinne B.,Russowsky, Dennis
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experimental part
p. 2484 - 2496
(2009/08/07)
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- SUBSTITUTED PIPERAZINES AND PIPERIDINES AS MODULATORS OF THE NEUROPEPTIDE Y2 RECEPTOR
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The invention provides novel non-peptidic NPY Y2 receptor inhibitors useful in treating or preventing: anxiolytic disorders or depression; injured mammalian nerve tissue; conditions responsive to treatment through administration of a neurotrophic factor; neurological disorders; bone loss; substance related disorders; sleep/wake disorders; cardiovascular disease; obesity; or an obesity-related disorder. Compounds of the invention are also useful in modulating endocrine functions, particularly endocrine functions controlled by the pituitary and hypothalamic glands, and are therefore useful in the treatment or prevention of inovulation and infertility.
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Page/Page column 27
(2010/11/27)
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- Benzofurans as suppressors of neurodegeneration
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A compound of the formula: wherein R1 and R2 each is H or a hydrocarbon group which may be substituted, or R1 and R2 form a 3- to 8-membered carbo or heterocyclic ring which may be substituted; R3 is H, a lower alkyl which may be substituted or an aromatic group which may be substituted; R4 is (1) an aromatic group which may be substituted, (2) an aliphatic hydrocarbon group substituted by an aromatic group which may be substituted, which hydrocarbon group may be further substituted or (3) an acyl; X and Y each is oxygen or sulfur which may be oxidized; and ring A is a benzene ring which may be further substituted, or a salt thereof, is useful for an agent for suppressing neurodegeneration.
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Page/Page column 37
(2010/10/20)
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- Privileged structure based ligands for melanocortin receptors - Substituted benzylic piperazine derivatives
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Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest
- Fisher, Matthew J.,Backer, Ryan T.,Collado, Ivan,De Frutos, Oscar,Husain, Saba,Hsiung, Hansen M.,Kuklish, Steve L.,Mateo, Ana I.,Mullaney, Jeffrey T.,Ornstein, Paul L.,Paredes, Cristina Garcia,O'Brian, Thomas P.,Richardson, Timothy I.,Shah, Jikesh,Zgombick, John M.,Briner, Karin
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p. 4973 - 4978
(2007/10/03)
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- Synthesis of New 4,5-Dihydro-3(2H)-pyridazinone Derivatives
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A novel series of compounds structurally related to nonpeptide angiotensin II (AII) receptor antagonists derived from 4,5-dihydro-3(2H)-pyridazinones has been prepared. In these compounds, the spacer is linked to the C4 of the heterocyclic ring.
- Meyer,Joussef,Gallardo,De Souza, L. De B. P.
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p. 783 - 793
(2007/10/03)
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- PROMOTERS FOR THE PROLIFERATION AND DIFFERENTIATION OF STEM CELLS AND/OR NEURON PRECURSOR CELLS
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An agent for promoting the proliferation or differentiation of a stem cell and/or neural progenitor cell, comprising a compound represented by Formula: wherein each of R1 and R2 is H, a hydrocarbon group or a heterocyclic group, or taken together with the adjacent carbon atom to form a ring, R3 is H, a hydrocarbon group or a heterocyclic group, W is a group represented by Formula: wherein Ring A is an optionally substituted benzene ring, Ring B is an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic ring, R4 is an acyl group having an aliphatic hydrocarbon group, which is substituted by an aromatic group and may have a further substitutent, or aromatic group, R5 is H, C1-6 alkyl or acyl, R4c is an aromatic group, an aliphatic hydrocarbon group or acyl, and X is O or S; Y is O, S or NH, Ring C is an optionally substituted benzene ring, or a salt or prodrug thereof is provided.
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- Selective ET(A) antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives
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The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ETA receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ETA antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC50 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC50 of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 μmol/kg) and was duly proposed and accepted as a development candidate.
- Astles, Peter C.,Brown, Thomas J.,Halley, Frank,Handscombe, Caroline M.,Harris, Neil V.,Majid, Tahir N.,McCarthy, Clive,McLay, Lain M.,Morley, Andrew,Porter, Barry,Roach, Alan G.,Sargent, Carol,Smith, Christopher,Walsh, Roger J. A.
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p. 900 - 910
(2007/10/03)
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- Six-membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives
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Phenoxyphenylacetic acids and derivatives of general structural formula I have endothelin STR1 antagonist activity and are therefore useful in treating cardiovascular disorders, such as hypertension, congestive heart failure, postischemic renal failure, vasospasm, cerebral and cardiac ischemia, myocardial infarction, inflammatory diseases, Raynaud's disease, and endotoxic shock, and asthma.
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- Processes for synthesizing substituted and unsubstituted aminoacetate esters
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Process for preparing certain substituted and unsubstituted aminoacetate esters. The esters can be used as intermediates for preparing herbicidal products.
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- SYNTHESES D'ESTERS OU D'ACIDES α-HALOGENES A PARTIR DES GEM DICYANO EPOXIDES.
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α-halogeno esters or α-halogenoacids were easily prepared by selective one pot reaction of gem-dicyano epoxides with halohydric acids in an alcoholic or aqueous media.
- Robert, A.,Jaguelin, S.,Guinamant, J. L.
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p. 2275 - 2282
(2007/10/02)
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