- Synthesis and in vitro biochemical evaluation of a series of alkyl 6-aminosulfonyl naphthanoates as potential inhibitors of human placental estrone sulfatase (ES)
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We report the tentative initial results of our on-going search for potent inhibitors of estrone sulfatase (ES), here we report a series of alkyl 6-aminosulfonyl naphthanoate-based compounds as potential inhibitors. The results suggest that the compounds are weak inhibitors in comparison to the standard compound used within the current study.
- Patel, Chirag K.,Ahmed, Sabbir
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Read Online
- C -Glycosylation of Substituted β-Naphthols with Trichloroacetimidate Glycosyl Donors
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Several glycosyl donors have been systematically investigated for C-glycosylation of substituted β-naphthols to delineate the effect of the substituents. Whereas glycosylations of the parent 2-naphthol are smoothly achievable, those of differently substituted 2-naphthols are cumbersome. Efficiency of the glycosylation depends on the nature of both the glycosyl donors and the substituents of the arene ring. Among various glycosyl donors, trichloroacetimidate glycosyl donors are found to be superior for glycosylation with substituted 2-naphthols.
- Chakraborty, Soumen,Mal, Dipakranjan
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Read Online
- Symmetrical mesogenic 2,5-bis(6-naphthalen-2-yl)-1,3,4-thiadiazoles
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Two series of new symmetrical 1,3,4-oxadiazoles 1a-n and 1,3,4-thiadiazoles 1b-n were prepared and their mesomorphic properties investigated by optical microscopy, differential scanning calorimetry, and powder X-ray diffractometry. Compounds 1b-n are kinetically more stable than compounds 1a-n. Compounds 1a-n exhibited monotropic nematic or smectic C phases, whereas, compounds 1b-n exhibited enantiotropic nematic or smectic A/smectic C phases. Compounds 1b-n have higher clearing temperatures and the larger temperature ranges of mesophases, which might be attributed to the better linearity and/or larger dipole, resulted from a more polarized sulfur atom than oxygen atom incorporated. The fluorescent properties of these two series of 1,3,4-thiadiazole/oxadiazole-based derivatives were also examined. The λmax peaks of the photoluminescence spectra for compounds 1a-6 and 1b-6 measured in THF occurred at ca. 385 nm and 423 nm, respectively. Both series were blue emitters.
- Kuo, Hsiu-Ming,Li, Sih-Yeh,Sheu, Hwo-Shuenn,Lai, Chung K.
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Read Online
- Construction, structure diversity, luminescent and dye absorption properties of coordination polymers comprising semi-rigid 6-(carboxymethoxy)-2-naphthoic acid
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Semi-rigid 6-(carboxymethoxy)-2-naphthoic acid (H2CNA) was successfully synthesized as a ligand containing O-bridging atom. Six coordination polymers based on H2CNA ligand and transition metal ions were successfully synthesized under the hydrothermal or solvothermal conditions, which named [Zn(CNA)]n (1), [Cd(CNA) (H2O)]n (2), [Co(HCNA)2(H2O)4] (3), [Ni(HCNA)2(H2O)4] (4), [Cu(CNA) (H2O)]n (5), [Ni(CNA) (H2O)]n (6). Single crystal structural analysis revealed that 1, 2, 5 and 6 are shown as 2D structures, and 3–4 displays 0D structures. All the structures assembled into 3D supramolecular networks by hydrogen bonding interaction. The thermal stability, luminescent properties and UV–vis spectra of these coordination polymers were discussed in detail. In addition, 5 has good adsorption ability for Congo Red with good selectivity.
- Jiao, Shaoshao,Li, Shaoxiang,Liu, Kang,Ma, Dingxuan,Wang, Lei,Yang, Bo,Zhang, Xinghao,Zhang, Yaowen
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- ION CHANNEL ANTAGONISTS/BLOCKERS AND USES THEREOF
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Provided are ion channel antagonists/blockers and uses thereof. Specifically, it provides the compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, preparation method therefor and application thereof. Definition of each group in the formula can be found in the specification for details. Provided is also pharmaceutical composition useful for treatment of heart disease and other ion channel related diseases.
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Page/Page column 22; 24; 71-73
(2021/06/22)
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- Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism
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Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.
- Schramm, Simon,Agnetta, Luca,Bermudez, Marcel,Gerwe, Hubert,Irmen, Matthias,Holze, Janine,Littmann, Timo,Wolber, Gerhard,Tr?nkle, Christian,Decker, Michael
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supporting information
p. 1349 - 1358
(2019/07/12)
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- α-Nitro-α,β-Unsaturated Ketones: An Electrophilic Acyl Transfer Reagent in Catalytic Asymmetric Friedel-Crafts and Michael Reactions
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Herein, we introduce α-nitro-α,β-unsaturated ketones as efficient electrophilic acyl transfer reagents, and they were employed in Friedel-Crafts as well as in Michael reactions. The desired acyl transfer products of these reactions were obtained in high yields with high to excellent enantioselectivities with t-leucine-derived squaramide catalyst under mild reaction conditions. Few applications including a synthesis of the isoxazoline motif have been demonstrated.
- Parida, Chandrakanta,Maity, Rajendra,Chandra Sahoo, Subas,Chandra Pan, Subhas
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supporting information
p. 6700 - 6704
(2019/09/07)
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- METHOD FOR PRODUCING 6-HYDROXY-2-NAPHTHOIC ACID ALKYL ESTER
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PROBLEM TO BE SOLVED: To provide a method for producing 6-hydroxy-2-naphthoic acid alkyl ester in high yield with and high production efficiency while inhibiting the occurrence of by-products. SOLUTION: A method for producing 6-hydroxy-2-naphthoic acid alkyl ester represented by formula (2) includes the step of, in the presence of an acid catalyst, making the reaction occur between 6-hydroxy-2-naphthoic acid of 1 molar equivalent and an aliphatic alcohol of 1.8-8.0 molar equivalents (where n is an integer of 1-6) SELECTED DRAWING: None COPYRIGHT: (C)2018,JPO&INPIT
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Paragraph 0075; 0076
(2018/03/24)
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- Differentially Substituted Phosphines via Decarbonylation of Acylphosphines
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A new route to phosphines was developed by a method that features a "pre-join and transform" process that proceeds via acylphosphine intermediates that may be readily prepared from carboxylic acids and disubstituted phosphines. The efficient decarbonylations of these acylphosphines using a nickel catalyst delivered the corresponding phosphines. This method shows that the carboxyl group can play a role similar to halides or triflates for introducing a substituted phosphorus atom on an aromatic ring.
- Yu, Rongrong,Chen, Xingyu,Martin, Stephen F.,Wang, Zhiqian
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p. 1808 - 1811
(2017/04/11)
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- Assembly and inhibitory activity of monovalent mannosides terminated with aromatic methyl esters: The effect of naphthyl groups
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A series of monovalent α-D-mannoside ligands terminated with aromatic methyl esters have been synthesized in excellent yields using the Cu(I) catalyzed azide-alkyne 1,3-dipolar cycloaddition (“click chemistry”). These mannosides were designed to have a unique aglycone moiety (tail) that combines a triazole ring attached to aromatic methyl esters via a six carbon alkyl chain. The mannose unit of these ligands was linked at the ortho, meta, and para positions of substituted methyl benzoates and 1-, 3-, and 6-substituted methyl 2-napthaoates. In hemagglutination assays, ligands (32A-38A) showed better inhibitory activities than the standard inhibitor, methyl α-D-mannopyranoside. Overall, the naphthyl-based mannoside ligand (37A) showed the best activity and therefore merits further development.
- Al-Mughaid, Hussein,Al-Zoubi, Raed M.,Khazaaleh, Maha,Grindley, T. Bruce
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- Bis[alkynylplatinum(II)] Terpyridine Molecular Tweezer/Guest Recognition Enhanced by Intermolecular Hydrogen Bonds: Phototriggered Complexation via the "caging" Strategy
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The binding affinity between alkynylplatinum(II) terpyridine molecular tweezer and naphthol-derived guests can be significantly enhanced by embedding an intermolecular O-H - -N hydrogen bond, facilitating the achievement of a responsive host-guest recognition system via the photolabile "caging" strategy.
- Fu, Tengfei,Han, Yifei,Ao, Lei,Wang, Feng
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supporting information
p. 2850 - 2853
(2016/10/12)
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- Rational design of partial agonists for the muscarinic M1 acetylcholine receptor
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Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy.
- Chen, Xinyu,Kl?ckner, Jessika,Holze, Janine,Zimmermann, Cornelia,Seemann, Wiebke K.,Schrage, Ramona,Bock, Andreas,Mohr, Klaus,Tr?nkle, Christian,Holzgrabe, Ulrike,Decker, Michael
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supporting information
p. 560 - 576
(2015/01/30)
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- Branched α-d-mannopyranosides: A new class of potent FimH antagonists
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FimH is a type I fimbrial lectin located at the tip of type-1 pili of uropathogenic Escherichia coli guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small-molecule antagonists is considered as a promising new therapeutic alternative to treat infections caused by uropathogenic Escherichia coli (UPEC). Herein we report that our recently disclosed α-d-mannopyranosides bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties act as potent FimH antagonists in vitro, as determined by a competitive binding assay on isolated FimH lectin. Most of the assayed compounds display FimH antagonistic activity in the range of 58-1000 nM. Based on the promising results of the first series of compounds, we have designed and synthesized a new series of asymmetrically disubstituted glyceryl α-d-mannopyranosides with improved physicochemical properties. Molecular docking calculations were employed to predict compounds' binding poses leading to two possible binding modes; so-called in- and out-docking modes in the "tyrosine gate" (formed by Tyr48 and Tyr137) for one aromatic moiety, which is in accordance with previous findings, while the second aromatic moiety reaches the previously unexplored lipophilic region formed by Phe142 and Ile13. Furthermore, compounds were found to be non-cytotoxic on HepG2 cells in concentrations up to 10 μM pointing to their selective toxicity, which is one of the key features of potential therapeutics for the treatment of urinary tract infections. This journal is the Partner Organisations 2014.
- Toma?i?, Tihomir,Rabbani, Said,Gobec, Martina,Ra??an, Irena Mlinari?,Podlipnik, ?rtomir,Ernst, Beat,Anderluh, Marko
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supporting information
p. 1247 - 1253
(2014/08/05)
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- N-heterocyclic carbene-assisted, Bis(phosphine)nickel-catalyzed cross-couplings of diarylborinic acids with aryl chlorides, tosylates, and sulfamates
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Efficient bis(phosphine)nickel-catalyzed cross-couplings of diarylborinic acids with aryl chlorides, tosylates, and sulfamates have been effected with an assistance of N-heterocyclic carbene (NHC) generated in situ from N,N′-dialkylimidazoliums, e.g., N-butyl-N′-methylimidazolium bromide ([Bmim]Br), in toluene using K3PO4·3H2O as base. In contrast to bis(NHC)nickel-catalyzed conventional Suzuki coupling of arylboronic acids, mono(NHC)bis(phosphine)nickel species generated in situ from Ni(PPh3)2Cl2/[Bmim]Br displayed high catalytic activities in the cross-couplings of diarylborinic acids. The structural influences from diarylborinic acids were found to be rather small, while electronic factors from aryl chlorides, tosylates, and sulfamates affected the couplings remarkably. The couplings of electronically activated aryl chlorides, tosylates, and sulfamates could be efficiently effected with 1.5 mol % NiCl2(PPh3)2/[Bmim]Br as catalyst precursor to give the biaryl products in excellent yields, while 3-5 mol % loadings had to be used for the couplings of non- and deactivated ones. A small ortho-substitutent on the aromatic ring of aryl chlorides, tosylates, and sulfamates was tolerable. Applicability of the nickel-catalyzed cross-couplings in practical synthesis of fine chemicals has been demonstrated in process development for a third-generation topical retinoid, Adapalene.
- Ke, Haihua,Chen, Xiaofeng,Zou, Gang
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p. 7132 - 7140
(2014/08/18)
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- Symmetric mesogenic twins derived from salicylaldimines
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The synthesis, characterization, and mesomorphic properties of a series of symmetric dimeric twins derived from mesogenic salicylaldimines 1a-e are reported. In order to understand the structure-property relations, the bridged spacer (m=5, 6, 7, 8, 9), an
- Kuo, Hsiu-Ming,Chu-Hsuan,Sheu, Hwo-Shuenn,Lai, Chung K.
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p. 4226 - 4235
(2013/06/27)
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- Discovery and mechanism study of SIRT1 activators that promote the deacetylation of fluorophore-labeled substrate
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SIRT1 is an NAD+-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKKac-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKK ac-AMC complex model based on the crystal structure. Km and Kd determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through π-stacking, while the other portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators.
- Wu, Jiahui,Zhang, Dengyou,Chen, Lei,Li, Jianneng,Wang, Jianling,Ning, Chengqing,Yu, Niefang,Zhao, Fei,Chen, Dongying,Chen, Xiaoyan,Chen, Kaixian,Jiang, Hualiang,Liu, Hong,Liu, Dongxiang
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supporting information
p. 761 - 780
(2013/04/10)
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- Oxofunctionalized trans-2-carboxycinnamic acids by catalytic domino oxidation of naphthols and hydronaphthoquinones
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(Chemical Equation Presented) The catalytic oxidation of naphthalenes was investigated. Hydrogen peroxide (30% aqueous) was used as an oxygen source, and 2,2′-dinitro-4,4′-ditrifluoromethyldiphenyl diselenide was the oxygen-transfer catalyst. Unsubstitute
- Giurg, Miroslaw,Muchalski, Hubert,Kowal, Ewa
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experimental part
p. 2526 - 2539
(2012/08/07)
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- Protecting group free synthesis of 6-substituted naphthols and binols
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A straightforward route for the preparation of 6-substituted naphthols and 6,6′-disubstituted binols (binol = 2,2′-dihydroxy-1,1′- binaphthyl) is presented. The synthesis has been accomplished by a one-step procedure starting from 6-bromo derivatives via direct lithiation with n-BuLi, followed by the addition of several electrophiles. This C-C functionalization has been successfully achieved with iodomethane, 3-methoxybenzaldehyde, benzophenone, methyl-2-methylbenzoate, methylbenzoate, dimethyl carbonate, ethyl 2-chloro-2-oxoacetate, and 2,2-dimethyloxirane (E). This reactivity offers a useful protecting group free synthetic protocol, toward chiral disubstituted 6,6′-binols with configuration retention of the binol moiety.
- Verga, Daniela,Percivalle, Claudia,Doria, Filippo,Porta, Alessio,Freccero, Mauro
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supporting information; experimental part
p. 2319 - 2323
(2011/05/14)
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- Bicyclic derivatives of the potent dual aromatase-steroid sulfatase inhibitor 2-bromo-4-{[(4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl} phenylsulfamate: Synthesis, SAR, crystal structure, and in vitro and in vivo activities
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The design and synthesis of a series of bicyclic ring containing dual aromatase-sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4-[(4-bromobenzyl)(4H-1,2,4-triazol-4-yl)amino] benzonitrile are reported. Biological evaluation with JEG-3 cells revealed structure-activity relationships. The X-ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures. In the sulfamate-containing series, compounds containing a naphthalene ring are both the most potent AI (39, IC50AROM=0.25 nm) and the best STS inhibitor (31, IC50STS=26 nm). The most promising DASI is 39 (IC50AROM= 0.25 nm, IC50STS=205 nm), and this was evaluated orally in vivo at 10 mgkg-1, showing potent inhibition of aromatase (93%) and STS (93%) after 3 h. Potent aromatase and STS inhibition can thus be achieved with a DASI containing a bicyclic ring system; development of such a DASI could provide an attractive new option for the treatment of hormone-dependent breast cancer.
- Wood, Paul M.,Woo, L. W. Lawrence,Labrosse, Jean-Robert,Thomas, Mark P.,Mahon, Mary F.,Chander, Surinder K.,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
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experimental part
p. 1577 - 1593
(2011/12/01)
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- Self-assembly of hybrid dendrons into doubly segregated supramolecular polyhedral columns and vesicles
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The synthesis and structural analysis of supramolecular dendrimers self-assembled from 3 libraries containing 20 first-generation hybrid dendrons are reported. Combinations of benzyl ether, naphthyl methyl ether, and biphenyl methyl ether repeat units wit
- Peterca, Mihai,Imam, Mohammad R.,Leowanawat, Pawaret,Rosen, Brad M.,Wilson, Daniela A.,Wilson, Christopher J.,Zeng, Xiangbing,Ungar, Goran,Heiney, Paul A.,Percec, Virgil
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supporting information; experimental part
p. 11288 - 11305
(2010/10/04)
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- Synthesis of 6-hydroxy-2-naphthoic acid from 2,6-diisopropylnaphthalene using NHPI as a key catalyst
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A new strategy to 6-hydroxy-2-naphthoic acid (HNPA) and 4-hydroxybenzoic acid from 2,6-diisopropylnaphthalene and p-cymene, respectively, was developed using the NHPI-catalyzed aerobic oxidation as a principal reaction. 2,6-Diisopropylnaphthalene was oxidized by the oxidation with O2 (1 atm) by NHPI (10 mol %) combined with Co(OAc)2 (0.5 mol %) to give 6-acetyl-2-isopropylnaphthalene, which then was converted to 6-isopropyl-2-naphthoic acid under O2 (1 atm) in the presence of Co(OAc)2 (0.5 mol %) and Mn(OAc)2 (0.5 mol %). Esterification of the resulting acid followed by the aerobic oxidation produced methyl 6-hydroxy-2-naphthoate whose hydrolysis led to the desired HNPA. An alternative route involves the oxidation of 6-acetyl-2-isopropylnaphthalene to 6-acetyl-2-naphthol on which subsequent oxidation and deacetylation gave HNPA. This method was successfully extended to the synthesis of 4-hydroxybenzoic acid from p-cymene.
- Nakamura, Ryota,Obora, Yasushi,Ishii, Yasutaka
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experimental part
p. 3577 - 3581
(2009/09/06)
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- Novel naphthalene-N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme
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Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition of D-glutamic acid (D-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA). Because of the high binding affinity of D-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted D-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure-activity relationships. The substituted naphthalene-N-sulfonyl-D-Glu inhibitors, which were synthesized as potential transitionstate analogues, displayed IC50 values ranging from 80 to 600 μM. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure-activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.
- Humljan, Jan,Kotnik, Miha,Contreras-Martel, Carlos,Blanot, Didier,Urleb, Uro?,Dessen, Andréa,?olmajer, Tom,Gobec, Stanislav
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supporting information; experimental part
p. 7486 - 7494
(2009/11/30)
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- VITAMIN D RECEPTOR MODULATORS
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The present invention relates to novel, non-secosteroidal, phenyl-naphthalene compounds of Formula (I): wherein R, R1, RP, ZP, LP1, LP2 LNP, RP3, RN, and ZNP are defined herein, their prepa
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Page/Page column 25
(2008/06/13)
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- Substituted naphthoic acid derivatives useful in the treatment of insulin resistance and hyperglycemia
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This invention provides compounds of Formula I having the structure wherein: R1 is hydroxyl, alkoxy of 1-4 carbons or —O(CH2)nX; n is an integer of 1-3; X is CONHR6 or CO2R6; R2
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Page/Page column 7
(2008/06/13)
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- COMPOUNDS WHICH MODULATE PPARγ TYPE RECEPTORS, AND USE THEREOF IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
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The invention relates to novel compounds that correspond to the general formula (I) below and to a method for preparing them, and to their use in pharmaceutical compositions intended for use in human or veterinary medicine (in dermatology, and also in the field of cardiovascular diseases, immune diseases and/or diseases associated with lipid metabolism), or alternatively in cosmetic compositions.
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- Biaromatic ligand activators of PPARgamma receptors
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Novel pharmaceutical/cosmetic compositions contain at least one biaromatic ligand activator of a PPARγ receptor, such biaromatic ligand having the structural formula (I): and are well suited, inter alia, for regulating and/or restoring skin lipid metabolism, for treating a wide variety of dermatological afflictions, and for preventing and/or treating the signs of aging and/or dry skin.
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- 2,6-QUINOLINYL AND 2,6-NAPHTHYL DERIVATIVES, PROCESSES FOR PREPARING THEM AND THEIR USES AS VLA-4 INHIBITORS
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The present invention concerns 2,6-quinolinyl and 2,6-naphthyl derivatives of formula (I), processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals for the treatment of VLA-4 dependent inflammatory diseases such as for example asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and atherosclerosis. Formula (I): wherein X is N or CH.
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Page/Page column 80
(2010/02/07)
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- NAPTHTHALENE DERIVATIVES WHICH INHIBIT THE CYTOKINE OR BIOLOGICAL ACTIVITY OF MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)
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Where Y, R1-R8 and R101-R108 are as defined in the specification. Compounds of formula (II) and methods of inhibiting the cytokine or biological activity of Macrophage Migrating Inhibitory Factor (MIF) comprising contacting MIF with a compound of formula (I) are provided. The invention also relates to methods of treating diseases or conditions where MIF cytokine or biological activity is implicated comprising administration of compounds of formula (I), either alone or as part of a combination therapy.
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- Process of synthesizing binaphthyl derivatives
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A process of synthesizing a compound of the formula 1: is disclosed, which comprises reacting a compound of the formula 2: with diphenylphosphine in the presence of an amine base and a nickel catalyst to produce a compound of formula 1.
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- Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif
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Examination of the PTP1B inhibitory potency of an extensive series of phosphotyrosyl (pTyr) mimetics (Xxx) expressed in the EGFr-derived hexapeptide platform Ac-Asp-Ala-Asp-Xxx-Leu-amide previously led to the finding of high inhibitory potency when Xxx = 4-(phosphonodifluoromethyl)phenylalanyl (F2Pmp) (Ki = 0.2 μM) and when Xxx = 3-carboxy-4-carboxy-methyloxyphenylalanyl (Ki = 3.6 μM). In the first instance, further work led from the F2Pmp-containing peptide to monomeric inhibitor, 6-(phosphonodifluoromethyl)-2-naphthoic acid (Ki = 22 μM), and to the pseudo-dipeptide mimetic, N-[6-(phosphonodifluoromethyl)-2-naphthoyl]-glutamic acid (Ki = 12 μM). In the current study, a similar approach was applied to the 3-carboxy-4-carboxymethyloxyphenylalanyl-containing peptide, which led to the preparation of monomeric 5-carboxy-6-carboxymethyloxy-2-naphthoic acid (Ki = 900 μM). However, contrary to expectations based on the aforementioned F2Pmp work, incorporation of this putative pTyr mimetic into the pseudo-dipeptide, N-[5-carboxy-6-carboxymethyloxy-2-naphthoyl]-glutamic acid, resulted in a substantial loss of binding affinity. A reevaluation of binding orientation for 5-carboxy-6-carboxymethyloxy-2-naphthoic acid was therefore undertaken, which indicated a 180° reversal of the binding orientation within the PTP1B catalytic site. In the new orientation, the naphthyl 2-carboxyl group, and not the o-carboxy carboxymethyloxy groups, mimics a phosphoryl group. Indeed, when 5-carboxy-2-naphthoic acid itself was examined at neutral pH for inhibitory potency, it was found to have Ki = 31 ± 7 μM, which is lower than parent 5-carboxy-6-carboxymethyloxy-2-naphthoic acid. In this fashion, 5-carboxy-2-naphthoic acid (or more appropriately, 6-carboxy-1-naphthoic acid) has been identified as a novel PTP1B binding motif.
- Gao,Voigt,Zhao,Pais,Zhang,Wu,Zhang,Burke Jr.
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p. 2869 - 2878
(2007/10/03)
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- Substituted 2-naphthoylguanidines, process for their preparation, their use as a medicament or diagnostic, and medicament containing them
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Substituted 2-naphthoylguanidines, process for their preparation, their use as a medicament or diagnostic, and medicament containing them Substituted 2-naphthoylguanidines of the formula I having the meanings indicated in claim 1 for R1 to R8, are suitabl
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- Amide derivatives and intermediates for the synthesis thereof
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Novel compounds which are amide derivatives represented by general formula (I) and medicinal preparations containing the same having an eosinophilic infiltration inhibitory effect based on a potent interferon (α,γ)-inducing activity and an exellent percutaneous absorbability and being efficacious in treating allergic inflammatory diseases such as atopic dermatitis, various tumors and viral diseases. In said formula, each symbol has the following meaning: R1 and R2 : each lower alkyl, etc.; X and Y: independently representing each oxygen, NR4, CR5 etc. (wherein R4 and R5 independently represent each hydrogen, an aromatic group, etc.); Z: an aromatic ring or heterocycle; R3 : hydrogen, lower alkoxy, etc.; g, i and k: independently representing each an integer of from 0 to 6; h, i and l: independently representing each an integer of 0 or 1; m: an integer of from 0 to 5; and n: an integer of from 2 to 12.
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- Piperidine-renin inhibitors compounds with improved physicochemical properties
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Piperidine renin inhibitors with heterocyclic core modifications or hydrophilic attachments show improved physical properties (lower lipophilicity, improved solubility). Tetrahydroquinoline derivative rac-30 with a molecular weight of 517 and a log D((pH 7.4)) of 1.9 displays potent and long lasting blood pressure lowering effects after oral administration to sodium depleted conscious marmosets.
- Gueller, Rolf,Binggeli, Alfred,Breu, Volker,Bur, Daniel,Fischli, Walter,Hirth, Georges,Jenny, Christian,Kansy, Manfred,Montavon, Francois,Mueller, Marcel,Oefner, Christian,Stadler, Heinz,Vieira, Eric,Wilhelm, Maurice,Wostl, Wolfgang,Maerki, Hans Peter
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p. 1403 - 1408
(2007/10/03)
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- Antifungal fusacandins
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Novel antifungal agents having the formula: STR1 wherein R is hydrogen or --C(O)--R1 wherein R1 is alkenyl, C2 -C12 -alkyl, aryl, arylalkenyl, arylalkyl, aryl-aryl-, arylalkoxy-aryl-, aryloxyl-aryl-, aryl-aryl-a
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- Arylamide inhibitors of HIV-1 integrase
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Based on data derived from a large number of HIV-1 integrase inhibitors, similar structural features can be observed, which consist of two aryl units separated by a central linker. For many inhibitors fitting this pattern, at least one aryl ring also requires orth obis-hydroxylation for significant inhibitory potency. The ability of such catechol species to undergo in situ oxidation to reactive quinones presents one potential limitation to their utility. In an effort to address this problem, a series of inhibitors were prepared which did not contain ortho bishydroxyls. None of these analogues exhibited significant inhibition. Therefore an alternate approach was taken, whose aim was to increase potency rather than eliminate catechol substructures. In this latter study, naphthyl nuclei were utilized as aryl components, since a previous report had indicated that fused bicyclic rings may afford higher affinity relative to monocyclic phenyl-based systems. In preliminary work with monomeric units, it was found that the 6,7-dihydroxy- 2-naphthoic acid (17) (IC50 = 4.7 μM) was approximately 10-fold more potent than its 5,6-dihydroxy isomer 19 (IC50 = 62.4 μM). Of particular note was the dramatic difference in potency between free acid 17 and its methyl ester 21 (IC50 > 200 μM). The nearly total loss of activity induced by esterification strongly indicates that the free carboxylic -OH is important for high potency of this compound. This contrasts with the isomeric 5,6-dihydroxy species 19, where esterification had no effect on inhibitory potency (23, IC50 = 52.7 μM). These data provide evidence that the monomeric 6,7- and 5,6-dihydroxynaphthalenes may be interacting with the enzyme in markedly different fashions. However, when these naphthyl nuclei were incorporated into dimeric structures, significant enhancements in potencies each relative to the monomeric acids were observed, with bis-6,7- dihydroxy analogue 49 and bis-5,6-dihydroxy analogue 51 both exhibiting approximately equal potencies (IC50 values of 0.81 and 0.11 μM, respectively).
- Zhao, He,Neamati, Nouri,Mazumder, Abhijit,Sunder, Sanjay,Pommier, Yves,Burke Jr., Terrence R.
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p. 1186 - 1194
(2007/10/03)
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- Multichromophoric cyclodextrins. 4. Light conversion by antenna effect
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A water soluble β-cyclodextrin (CD-NA) bearing seven naphthoyl chromophores forms very stable 1:1 complexes with a merocyanine laser dye DCM-OH (4-(dicyanomethylene)-2-methyl-6-(p-(bis(hydroxyethyl)amino)-styryl)-4 H-pyran). The antenna effect, i.e. energ
- Jullien, Ludovic,Canceill, Josette,Valeur, Bernard,Bardez, Elisabeth,Lefèvre, Jean-Pierre,Lehn, Jean-Marie,Marchi-Artzner, Valérie,Pansu, Robert
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p. 5432 - 5442
(2007/10/03)
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- Optically active naphthalene compounds and liquid crystal materials and devices incorporating them
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Optically active naphthalene compounds having the formula: STR1 in which X and Y are selected from combinations (a), (b) and (c): (a) X is C1-10 alkyl or alkoxy and Y is C4-16 optically active alkyl, (b) X is C1-10 alkyl o
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- Preparation of hydroxy aromatic carboxylic acids and ester derivatives thereof
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A process for preparing hydroxy aromatic carboxylic acids, or the ester derivatives thereof, comprises carbonylating a hydroxy aromatic halide in the presence of a reactive alcohol solvent and a catalytic amount of a Group VIII metal catalyst. The process has particular applicability to the preparation of 6-hydroxy-2-naphthoic acid from 6-bromo-2-naphthol, which can be easily prepared from β-naphthol, a readily available and inexpensive starting material.
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