- Computer-Aided Fragment Growing Strategies to Design Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase
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Multitarget ligands are interesting candidates for drug discovery and development due to improved safety and efficacy. However, rational design and optimization of multitarget ligands is tedious because affinity optimization for two or more targets has to be performed simultaneously. In this study, we demonstrate that, given a molecular fragment, which binds to two targets of interest, computer-aided fragment growing can be applied to optimize compound potency, relying on either ligand- or structure-derived information. This methodology is applied to the design of dual inhibitors of soluble epoxide hydrolase and leukotriene A4 hydrolase.
- Hefke, Lena,Hiesinger, Kerstin,Kramer, Jan S.,Proschak, Ewgenij,Zhu, W. Felix
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Read Online
- Suppression effect of the Pd/C-catalyzed hydrogenolysis of a phenolic benzyl protective group by the addition of nitrogen-containing bases
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A mild and chemoselective hydrogenation method using 5% Pd/C for olefin, N-Cbz, benzyl ester and nitro functionalities distinguishing from the benzyl protective group for the phenolic hydroxyl group has been developed by the employment of 2,2'-dipyridyl as an additive. The suppressive effect on the benzyl ether hydrogenolysis was strongly influenced by the sorts of nitrogen- containing bases employed as an additive.
- Sajiki, Hironao,Kuno, Hiroko,Hirota, Kosaku
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Read Online
- Discovery of Salidroside-Derivated Glycoside Analogues as Novel Angiogenesis Agents to Treat Diabetic Hind Limb Ischemia
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Therapeutic angiogenesis is a potential therapeutic strategy for hind limb ischemia (HLI); however, currently, there are no small-molecule drugs capable of inducing it at the clinical level. Activating the hypoxia-inducible factor-1 (HIF-1) pathway in skeletal muscle induces the secretion of angiogenic factors and thus is an attractive therapeutic angiogenesis strategy. Using salidroside, a natural glycosidic compound as a lead, we performed a structure-activity relationship (SAR) study for developing a more effective and druggable angiogenesis agent. We found a novel glycoside scaffold compound (C-30) with better efficacy than salidroside in enhancing the accumulation of the HIF-1α protein and stimulating the paracrine functions of skeletal muscle cells. This in turn significantly increased the angiogenic potential of vascular endothelial and smooth muscle cells and, subsequently, induced the formation of mature, functional blood vessels in diabetic and nondiabetic HLI mice. Together, this study offers a novel, promising small-molecule-based therapeutic strategy for treating HLI.
- Liu, Caiping,Han, Jingxuan,Marcelina, Olivia,Nugrahaningrum, Dyah Ari,Huang, Song,Zou, Meijuan,Wang, Guixue,Miyagishi, Makoto,He, Yun,Wu, Shourong,Kasim, Vivi
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p. 135 - 162
(2022/01/14)
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- Unintended Formation of a 26-Membered Cycle in the Course of a Novel Approach to Myricanol, a Strained [7,0]-Metacyclophane
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A convergent approach for the synthesis of (±)-myricanol, a strained diarylheptanoid isolated from Myricacae, was undertaken using a Suzuki-Miyaura coupling followed by a ring-closing metathesis (RCM). Herein, we report the unintentional formation of a 26-membered macrocycle as RCM product resulting from a head-to-tail dimerization of the seco -precursor, even in relay ring-closing metathesis (RRCM) conditions.
- Chiummiento, Lucia,Choppin, Sabine,Colobert, Fran?oise,Hanquet, Gilles,Massé, Paul
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supporting information
p. 559 - 564
(2020/03/27)
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- Benzoic hydroxamate-based iron complexes as model compounds for humic substances: Synthesis, characterization and algal growth experiments
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A series of monomeric and dimeric FeIII complexes bearing benzoic hydroxamates as O,O-chelates has been prepared and characterized by elemental analysis, IR spectroscopy, UV-Vis spectroscopy, electrospray ionization mass spectrometry (ESI-MS), cyclic voltammetry, EPR spectroscopy and for some examples by X-ray diffraction analysis. The stability of the synthesized complexes in pure water and seawater was monitored over 24 h by means of UV-Vis spectrometry. The ability to release iron from the synthesized model complexes has been investigated with algae growth experiments.
- Orlowska, Ewelina,Roller, Alexander,Wiesinger, Hubert,Pignitter, Marc,Jirsa, Franz,Krachler, Regina,Kandioller, Wolfgang,Keppler, Bernhard K.
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p. 40238 - 40249
(2016/05/24)
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- COMPOUND EXHIBITING REGULATORY ACTIVITY ON LYSOPHOSPHATIDYLSERINE RECEPTOR FUNCTION
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The object of the present invention is to provide a compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof. A compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof, or a pharmaceutical composition or a lysophosphatidylserine receptor function moderator containing such compound or salt is provided by the present invention.
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Paragraph 0217
(2015/12/19)
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- ALKANOIC ACID DERIVATIVES AND THEIR THERAPEUTIC USE AS HDAC INHIBITORS
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The invention related to alkanoic acid derivatives of Formula (IIa) and (IIb). These compounds of the invention were found to have activity as HDAC inhibitors.
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Page/Page column 104
(2010/08/05)
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- Structure-activity study of dihydrocinnamic acids and discovery of the potent FFA1 (GPR40) agonist TUG-469
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The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29).
- Christiansen, Elisabeth,Due-Hansen, Maria E.,Urban, Christian,Merten, Nicole,Pfleiderer, Michael,Karlsen, Kasper K.,Rasmussen, Sanne S.,Steensgaard, Mette,Hamacher, Alexandra,Schmidt, Johannes,Drewke, Christel,Petersen, Rasmus Koefoed,Kristiansen, Karsten,Ullrich, Susanne,Kostenis, Evi,Kassack, Matthias U.,Ulven, Trond
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scheme or table
p. 345 - 349
(2010/12/19)
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- Discovery of azetidinone acids as conformationally-constrained dual PPARα/γ agonists
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A novel class of azetidinone acid-derived dual PPARα/γ agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARα and PPARγ receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
- Wang, Wei,Devasthale, Pratik,Farrelly, Dennis,Gu, Liqun,Harrity, Thomas,Cap, Michael,Chu, Cuixia,Kunselman, Lori,Morgan, Nathan,Ponticiello, Randy,Zebo, Rachel,Zhang, Litao,Locke, Kenneth,Lippy, Jonathan,O'Malley, Kevin,Hosagrahara, Vinayak,Zhang, Lisa,Kadiyala, Pathanjali,Chang, Chiehying,Muckelbauer, Jodi,Doweyko, Arthur M.,Zahler, Robert,Ryono, Denis,Hariharan, Narayanan,Cheng, Peter T.W.
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p. 1939 - 1944
(2008/09/20)
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- SUBSTITUTED BIPHENYL PHENOXY-, THIOPHENYL- AND AMINOPHENYLPROPANOIC ACID GPR40 MODULATORS
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The present invention provides compounds useful, for example, for treating metabolic disorders in a subject. Such compounds have the general formula (I) where the definitions of the variables are provided herein. The present invention also provides compositions that include, and methods for using, the compounds in preparing medicaments and for treating metabolic disorders such as, for example, type II diabetes.
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Page/Page column 104
(2008/12/08)
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- TETRACYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE
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Certain tetracyclic compounds are described, which may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).
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Page/Page column 39
(2009/01/20)
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- Structure-activity relationships of α-ketooxazole inhibitors of fatty acid amide hydrolase
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A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, K, - 2.6 nM), with 5hh (aryl -3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
- Hardouin, Christophe,Kelso, Michael J.,Romero, F. Anthony,Rayl, Thomas J.,Leung, Donmienne,Hwang, Inkyu,Cravatt, Benjamin F.,Boger, Dale L.
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p. 3359 - 3368
(2008/02/13)
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- AGENT FOR CONTROLLING FUNCTION OF GPR34 RECEPTOR
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The present invention provides a GPR receptor function regulator comprising the compound represented by the formula: [wherein ring A is an optionally substituted isocyclic or heterocyclic ring, P is a bond or spacer, ring D is an optionally substituted monocyclic aromatic ring which may be condensed with a 5-to 7-membered ring, V is a bond or the group represented by the formula -CR14=CR15 - or - N=CR16- (wherein R14, R15 and R16 each represents a hydrogen atom or optionally substituted hydrocarbon group), Q is a bond or spacer, and W is a carboxyl or a group biologically equivalent to a carboxyl] or its salt or a prodrug thereof
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Page/Page column 81
(2010/11/28)
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- RECEPTOR FUNCTION REGULATING AGENT
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An agent for regulating 14273 receptor function, which is useful as a preventing or treating drug for diabetes mellitus, hyperlipidemia or the like, is provided. An agent for regulating 14273 receptor function comprising a compound containing an aromatic ring and a group capable of releasing a cation.
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Page/Page column 76
(2010/11/23)
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- Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same
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The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1 and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula 1, and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.
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Page/Page column 153
(2008/06/13)
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- Galanthamine analogs: 6H-benzofuro[3a,3,2,-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine
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The known cholinesterase inhibitory capability of the Amarylidaceae alkaloid galanthamine prompted preparation of analogs in which the position of the nitrogen within the azepine ring is altered. The analogs 6H-benzofuro[3a,3,2-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3] benzazepine were prepared in 19 and 2.5%, respectively, following Kametani and Shimizu approaches, respectively. The aniline derivative 6H-benzofuro[3a,3,2-e, f][1]benzazepine failed to undergo most of the reactions typical for galanthamine. Thus, it neither oxidized to the analogous narwedine, nor epimerized to the analogous epigalanthamine, nor reduced to the lycoramine analog, under the conditions used for galanthamine.
- Lewin, Anita H.,Szewczyk, Jerzy,Wilson, Joseph W.,Carroll, F. Ivy
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p. 7144 - 7152
(2007/10/03)
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- RECEPTOR FUNCTION CONTROLLING AGENT
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The GPR40 receptor function regulator of the present invention, which comprises a compound having an aromatic ring and a group capable of releasing cation is useful as an insulin secretagogue or an agent for the prophylaxis or treatment of diabetes and the like.
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Page/Page column 70
(2008/06/13)
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- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
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The invention relates to compounds of the formula (I) and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula (I), and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula (I). The invention also relates to methods of preparing the compounds of formula (I).
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Page 316-317
(2008/06/13)
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- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
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Compounds of formula (I) are hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors, and are useful in therapeutic and prophylactic treatment of persons infected with hepatitis C virus.
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Page/Page column 15-16
(2010/02/07)
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- AMIDE LINKER PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR MODULATORS
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The present invention is directed to compounds, compositions, and use of compounds the structural Formula (I).
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- Alpha-and beta- substituted trifluoromethyl ketones as phospholipase inhibitors
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Inhibitors of the cytosolic phospholipase A2 enzymes are provided which are of use in controlling a wide variety of inflammatory diseases. The inhibitors of the present invention have the general formula where X, Z, R1, R2, R3, R4, Ra and Rb are as defined in the specification.
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- Alpha-and beta-substituted trifluoromethyl ketones as phospholipase inhibitors
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Inhibitors of the cytosolic phospholipase A2 enzymes are provided which are of use in controlling a wide variety of inflammatory diseases. The inhibitors of the present invention have the general formula where X, Z, R1, R2, R3, R4, Raand Rbare as defined in the specification.
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- Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1′, a series of selective TNF-α converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-α release
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SAR exploration at P1′ using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1′ derivatives which confer potent porcine TACE and anti-TNF-α cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1′ pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1′ residues.
- Xue,He,Corbett,Roderick,Wasserman,Liu,Jaffee,Covington,Qian,Trzaskos,Newton,Magolda,Wexler,Decicco
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p. 3351 - 3354
(2007/10/03)
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- A novel type of Pd/C-catalyzed hydrogenation using a catalyst poison: Chemoselective inhibition of the hydrogenolysis for O-benzyl protective group by the addition of a nitrogen-containing base
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A mild and chemoselective hydrogenation method for a variety of reducible functional groups distinguishing front aliphatic and aromatic' benzyl ethers was accomplished by the addition of an appropriate nitrogen- containing base to the Pd/C-catalyzed hydrogenation system.
- Sajiki, Hironao,Hirota, Kosaku
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p. 13981 - 13996
(2007/10/03)
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- THE BIOSYNTHESIS OF SCELETIUM ALKALOIDS IN SCELETIUM SUBVELUTINUM L. BOLUS
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Six Sceletium (Mesembrine) alkaloids (1)-(6) are identified, together with N,N-dimethyltyramine (10), as constituents of Sceletium subvelutinum.The alkaloids (1)-(6) incroporate label from tyramine and 3-(-4-hydroxyphenyl)propionic acid (13) as expected; notably 3-(-4-hydroxyphenyl)propanal (15) is a more efficient alkaloid precursor than is the acid (13) and the aldehyde is deduced to be a key intermediate in the biosynthesis of Sceletium alkaloids.The N-methylamine (21) is an important late intermediate in the biosynthesis of Sceletium alkaloids, or is closely related to that intermediate.The amine (2) is less efficiently incorporated than (22)=(21) is.
- Herbert, Richard B.,Kattah, Abdullah E.
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p. 7105 - 7118
(2007/10/02)
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- Isoquinolinium Salt Syntheses from Cyclopalladated Benzaldimines and Alkynes
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Cyclopalladated, N-substituted benzaldimine tetrafluoroborates react with disubstituted alkynes in poor to good yields to form isoquinolinium tetrafluoroborates.The reaction is particularly useful for preparing trisubstituted products.Electron-donating substituens may be presented at the 5, 6, 7, and 8 positions, as well.Methyl (p-benzoxyphenyl)propiolate adds to cyclopalladated N-methyl-3-benzoxy-4-methoxybenzaldimine tetrafluoroborate to form the 3-arylisoquinolinium salt. 3-Hexyne reacts with cyclopalladated N-phenylbenzaldymine chloro dimer at 150 deg C to form the isoquinolinium chloride but at less than half (29percent) the yield that is obtained from the corresponding tetrafluoroborate.
- Wu, Guangzhong,Geib, Steven J.,Rheingold, Arnold L.,Heck, Richard F.
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p. 3238 - 3241
(2007/10/02)
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- A Study on Horseradish Peroxidase-mediated Coupling of Phenolesters, Directed to Synthesis of Lythraceae Alkaloids
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Phenolesters 2, 6 and 13 were used as substrates for the oxidative coupling by means of horseradish peroxidase/hydrogen peroxide system (HRPO/H2O2).The results are discussed from the viewpoint of the possible applications of phenolesters as model compounds for the synthesis of Lythraceae alkaloids.
- Krawczyk, Andrzej R.,Lipkowska, Ewa,Wrobel, Jerzy T.
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p. 115 - 122
(2007/10/02)
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- Studies on the Chemical Constituents of Rutaceous Plants. Part 45. Novel Phenyl Propanoids: Cuspidiol, Boninenal, and Methyl Boninenalate
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Cuspidiol, boninenal, and methyl boninenalate were established as having the structures 3-phenyl>propanol (1), (E)-3-phenyl>propenal (2), and (E)-3-phenyl>propenal (3) respectively.The three compounds were also independently synthesized.
- Ishii, Hisashi,Ishikawa, Tsutomu,Tohojoh, Toshiaki,Murakami, Keiko,Kawanable, Eri,et al.
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p. 2051 - 2058
(2007/10/02)
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- Hypolipidemic analogues of ethyl 4 benzyloxybenzoate
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A series of compounds related to ethyl 4-benzyloxybenzoate was synthesized and evaluated for potential hypolipidemic activity in rats. Structure-activity relationships are discussed in terms of cholesterol-lowering activity together with effects on body weight gain and liver lipids. A number of the compounds inhibited cholesterol and free fatty acid biosynthesis from [1-14C]acetate in rat liver slices in vitro. Ethyl 4-benzyloxybenzoate, ethyl 4-benzyloxybenzoic acid, ethyl 4-p-bromobenzyloxybenzoate, and ethyl 4-o-methoxybenzyloxyphenyl acetate exhibited the most favorable spectrum of activity.
- Baggaley,Fears,Hindley,Morgan,Murrell,Thorne
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p. 1388 - 1393
(2007/10/05)
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