- PANTETHEINE DERIVATIVES AND USES THEREOF
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The present disclosure relates to compounds of Formula (I), (II), or (II'): (I), (II), (II'), and pharmaceutically acceptable salts or solvates thereof. The present disclosure also relates to pharmaceutical compositions comprising the compounds and therapeutic and diagnostic uses of the compounds and pharmaceutical compositions.
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Paragraph 2121
(2020/06/19)
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- Spontaneously Blinking Fluorophores Based on Nucleophilic Addition/Dissociation of Intracellular Glutathione for Live-Cell Super-resolution Imaging
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Single-molecule localization microscopy (SMLM) allows the reconstruction of super-resolution images but generally requires prior intense laser irradiation and in some cases additives to induce blinking of conventional fluorophores. We previously introduced a spontaneously blinking rhodamine fluorophore based on an intramolecular spirocyclization reaction for live-cell SMLM under physiological conditions. Here, we report a novel principle of spontaneous blinking in living cells, which utilizes reversible ground-state nucleophilic attack of intracellular glutathione (GSH) upon a xanthene fluorophore. Structural optimization afforded two pyronine fluorophores with different colors, both of which exhibit equilibrium (between the fluorescent dissociated form and the nonfluorescent GSH adduct form) and blinking kinetics that enable SMLM of microtubules or mitochondria in living cells. Furthermore, by using spontaneously blinking fluorophores working in the near-infrared (NIR) and green ranges, we succeeded in dual-color live-cell SMLM without the need for optimization of the imaging medium.
- Morozumi, Akihiko,Kamiya, Mako,Uno, Shin-Nosuke,Umezawa, Keitaro,Kojima, Ryosuke,Yoshihara, Toshitada,Tobita, Seiji,Urano, Yasuteru
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supporting information
p. 9625 - 9633
(2020/07/25)
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- Cationic Lipid
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The present invention provides a cationic lipid which is able to be used for nucleic acid delivery to the cytoplasm. A cationic lipid according to the present invention is, for example, a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, wherein L1 and L2 independently represent an alkylene group having 3 to 10 carbon atoms; R1 and R2 independently represent an alkyl group having 4 to 24 carbon atoms or an alkenyl group having 4 to 24 carbon atoms; R3 represents an alkyl group having 1 to 3 carbon atoms; and X1 represents a single bond or CO—O—.
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Paragraph 0189-0191
(2020/11/24)
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- CATIONIC LIPID
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The present invention provides a cationic lipid which is able to be used for nucleic acid delivery to the cytoplasm. A cationic lipid according to the present invention is, for example, a compound represented by formula (1a) or a pharmaceutically acceptable salt thereof. (In formula (1a), each of L1 and L2 independently represent an alkylene group having 3-10 carbon atoms; each of R1 and R2 independently represent an alkyl group having 4-22 carbon atoms or an alkenyl group having 4-22 carbon atoms; X1 represents a single bond or -CO-O-; and ring P represents one of formulae (P-1) to (P-5).)(In formulae (P-1) to (P-5), R3 represents an alkyl group having 1-3 carbon atoms.)
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Paragraph 0148; 0149
(2019/05/10)
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- Cation-π interactions contribute to substrate recognition in γ-butyrobetaine hydroxylase catalysis
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γ-Butyrobetaine hydroxylase (BBOX) is a non-heme FeII- and 2-oxoglutarate-dependent oxygenase that catalyzes the stereoselective hydroxylation of an unactivated C-H bond of γ-butyrobetaine (γBB) in the final step of carnitine biosynthesis. BBOX contains an aromatic cage for the recognition of the positively charged trimethylammonium group of the γBB substrate. Enzyme binding and kinetic analyses on substrate analogues with P and As substituting for N in the trimethylammonium group show that the analogues are good BBOX substrates, which follow the efficiency trend N+>P+>As+. The results reveal that an uncharged carbon analogue of γBB is not a BBOX substrate, thus highlighting the importance of the energetically favorable cation-π interactions in productive substrate recognition. What's in the BBOX? Enzyme kinetics and substrate binding studies reveal that γ-butyrobetaine hydroxylase (BBOX)-catalyzed stereoselective hydroxylation of γ-butyrobetaine involves energetically favorable cation-π interactions.
- Kamps, Jos J. A. G.,Khan, Amjad,Choi, Hwanho,Lesniak, Robert K.,Brem, Jürgen,Rydzik, Anna M.,McDonough, Michael A.,Schofield, Christopher J.,Claridge, Timothy D. W.,Mecinovic, Jasmin
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supporting information
p. 1270 - 1276
(2016/01/25)
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- CRYSTALLINE FORMS OF A THERAPEUTIC COMPOUND AND USES THEREOF
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Disclosed herein are certain crystalline forms of Compound 5, N-(5-((2-(4-(2-oxa-7- azaspiro[3.5]nonan-7-yl)butanamido)imidazo[1,2-0]pyridazin-6-yl)oxy)-2-methylphenyl)-1,3- dimethyl-1 /-/-pyrazole-5-carboxamide, as well as pharmaceutical compositions comprising the crystalline forms. The present disclosure further relates to methods for treating or preventing diseases or disorders using the crystalline forms or pharmaceutical compositions thereof in a subject in need thereof, including diseases or disorders associated with abnormal or pathological angiogenesis and/or aberrant signaling of a growth factor signaling pathway (e.g., vascular endothelial growth factor (VEGF)), such as proliferative diseases and ocular diseases.
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Paragraph 00140
(2016/06/14)
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- Synthesis and evaluation of phenoxymethylbenzamide analogues as anti-trypanosomal agents
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The synthesis and anti-trypanosomal activity of a compound library based on a phenoxymethylbenzamide hit discovered in a high throughput screen is described. Several of the analogues exhibited potent activity against Trypanosoma brucei rhodesiense, a human infective strain of the trypanosome parasite, that serve as lead compounds for further optimisation. This journal is
- Manos-Turvey, Alexandra,Watson, Emma E.,Sykes, Melissa L.,Jones, Amy J.,Baell, Jonathan B.,Kaiser, Marcel,Avery, Vicky M.,Payne, Richard J.
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supporting information
p. 403 - 406
(2015/03/18)
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- MRI CONTRAST AGENTS
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The present invention relates to MRI based imaging. In particular, the present invention provides MRI contrast agents targeted to a HaloTag protein with tunable relaxation properties thereby providing optimal relaxivity for low field strength imaging and the other optimal relaxivity for high field strength imaging. Moreover, the MRI contrast agents are used to detect gene expression (of a gene of interest) in real time in vivo, to detect changes in gene expression (of a gene of interest) over time in, for example, an individual organism, to detect gene expression changes (of a gene of interest) in response to therapeutics, in cell labeling for MR imaging, in clinical diagnostics, and in theranostics.
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Paragraph 0102; 0103; 0104; 0105; 0106
(2013/11/19)
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- Reporter protein-targeted probes for magnetic resonance imaging
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Contrast agents for magnetic resonance imaging are frequently employed as experimental and clinical probes. Drawbacks include low signal sensitivity, fast clearance, and nonspecificity that limit efficacy in experimental imaging. In order to create a bioresponsive MR contrast agent, a series of four Gd(III) complexes targeted to the HaloTag reporter were designed and synthesized. HaloTag is unique among reporter proteins for its specificity, versatility, and the covalent interaction between substrate and protein. In similar systems, these properties produce prolonged in vivo lifetimes and extended imaging opportunities for contrast agents, longer rotational correlation times, and increases in relaxivity (r1) upon binding to the HaloTag protein. In this work we report a new MR contrast probe, 2CHTGd, which forms a covalent bond with its target protein and results in a dramatic increase in sensitivity. A 6-fold increase in r1, from 3.8 to 22 mM-1s-1, is observed upon 2CHTGd binding to the target protein. This probe was designed for use with the HaloTag protein system which allows for a variety of substrates (specific for MRI, florescence, or protein purification applications) to be used with the same reporter.
- Strauch, Renee C.,Mastarone, Daniel J.,Sukerkar, Preeti A.,Song, Ying,Ipsaro, Jonathan J.,Meade, Thomas J.
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supporting information; experimental part
p. 16346 - 16349
(2011/12/14)
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- Tuning the polarity of hierarchically assembled helicates
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Catechol ligands bearing ester groups in 3-position (1a,b, 2) are building blocks for the formation of triply lithium-bridged dinuclear helicate-type complexes [Li1a,b,2)i-. Attachment of appropriate functionalities at the ester unit allows the fine tuning of the polarity of the compounds to afford solubility in highly nonpolar as well as highly polar solvents. The investigations show that the internal dinuclear core is stable in a broad variety of solvents, even in water. Georg Thieme Verlag Stuttgart ? New York.
- Baumert, Miriam,Albrecht, Markus,Winkler, Henrik D. F.,Schalley, Christoph A.
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experimental part
p. 953 - 958
(2010/06/11)
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- Backbone amide linker strategy for the synthesis of 1,4-triazole-containing cyclic tetra- and pentapeptides
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A backbone amide linker strategy was chosen for the solid-phase synthesis of triazole-containing cyclic tetra- and pentapeptides. An alkyne-substituted linker derived from 4-hydroxy-2-methoxybenzaldehyde was elongated by using standard Fmoc-based solid phase chemistry and terminated by coupling of an azido acid. In solution, the peptides were cyclized by a Cu I-catalyzed azide-alkyne cycloaddition reaction. The solid-supported synthesized linear peptides had to be cleaved prior to cyclization. As an example of cyclic tetrapeptides, a triazole analog of cyclo-[Pro-Val-Pro-Tyr] (2) was prepared by the solid-phase/solution-phase method. For the cyclic pentapeptides, segetalin B (3) was chosen as a model compound to show the applicability of this method. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Springer, Jasper,De Cuba, Kimberly R.,Calvet-Vitale, Sandrine,Geenevasen, Jan A. J.,Hermkens, Pedro H. H.,Hiemstra, Henk,Van Maarseveen, Jan H.
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experimental part
p. 2592 - 2600
(2009/04/05)
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- A new method for constructing quaternary carbon centres: Tandem rhodium-catalysed 1,4-addition/intramolecular cyclisation
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The efficient tandem rhodium-catalysed 1,4-addition/cyclisation of 1,1′-alkenes using arylzinc chlorides is described. The simple one-step synthesis of substituted cyclopentanone and cyclohexanone derivatives is performed from acyclic precursors using relatively low catalyst loadings under mild conditions. A new quaternary carbon centre is created during the cyclisation step.
- Le Notre, Jerome,Van Mele, David,Frost, Christopher G.
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p. 432 - 440
(2008/02/07)
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- Nitric oxide enhancing diuretic compounds, compositions and methods of use
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The invention describes novel compositions and kits comprising at least one nitric oxide enhancing diuretic compound, or pharmaceutically acceptable salts thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The invention also provides methods for (a) treating conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidative stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (l) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; (p) treating metabolic syndrome; (q) treating sexual dysfunctions; and (r) hyperlipidemia. The nitric oxide enhancing diuretic compounds comprise at least one nitric oxide enhancing group linked to the diuretic compound through one or more sites such as carbon, oxygen and/or nitrogen via a bond or moiety that cannot be hydrolyzed.
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Page/Page column 57
(2008/06/13)
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- NITROGENOUS FUSED-RING DERIVATIVES, MEDICINAL COMPOSITIONS CONTAINING THE DERIVATIVES, AND USE THEREOF AS DRUGS
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The present invention provides nitrogen-containing fused-ring derivatives represented by the following general formula, or pharmaceutically acceptable salts thereof, or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic complications or obesity, in the formula R 1 represent H, an optionally substituted alkyl group, an alkenyl group, etc.; R 2 represent H, a halogen atom or an alkyl group; R 3 and R 4 represent H, OH, a halogen atom, an optionally substituted alkyl group, etc. ; Y represents CH or N; Q represents alkylene, alkenylene, etc.; ring A represents an aryl group or a heteroaryl group; G represents a group represented by the following general formula (G-1)or(G-2) (in which E 1 represents H, F or OH; and E 2 represents H, F, a methyl group, etc.), and pharmaceutical compositions comprising the same, and pharmaceutical uses thereof.
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Page/Page column 44-45
(2010/11/24)
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- PYRAZOLE DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME, MEDICINAL USE THEREOF, AND INTERMEDIATE FOR PRODUCTION THEREOF
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The present invention provides pyrazole derivatives represented by the general formula: wherein R1 represents H, an optionally substituted C1-6 alkyl group etc.; one of Q and T represents a group represented by the general formula: or a group represented by the general formula: while the other represents an optionally substituted C1-6 alkyl group etc.; R2 represents H, a halogen atom, OH, an optionally substituted C1-6 alkyl group etc.; X represents a single bond, O or S; Y represents a single bond, a C1-6 alkylene group etc. ; Z represents CO or SO2; R4 and R5 represent H, an optionally substituted C1-6 alkyl group etc.; and R3, R6 and R7 represent H, a halogen atom etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT1 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, diabetic complications or obesity, and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.
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Page/Page column 58
(2008/06/13)
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- Non-nucleoside reverse transcriptase inhibitors
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Non-nucleoside reverse transcriptase inhibitors of formula (P-1) wherein: Ar1 is an unsaturated, optionally substituted, mono or bicyclic ring structure comprising 0 to 3 hetero atoms selected from S, O and N; Ar2 is an aromatic, optionally substituted, monocyclic ring structure comprising at least one nitrogen hetero atom and zero to two further hetero atoms selected from S, O and N; R4 and R5 are independently H or C3-C8 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C5 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkylthio, amino, carboxy, carbamoyl, cyano, halo, hydroxy, aminomethyl, hydroxymethyl, carboxymethyl, or halo substituted C1-C6 alkyl mercapto, nitro; or R4 and RS join to form a 3-6 membered, optionally substituted ring structure; R6 is 0 or S; Rx is the residue of a natural or unnatural amino acid; and L* is a linker moiety which is ether-, carbonate- or ester-bound to the adjacent oxygen and ester linked to Rx; and pharmaceutically acceptable salts thereof are anti-HIV agents with favourable pharmacokinetic properties.
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- 8-aza-bicyclo[3.2.1]octane NMDA/NR2B antagonists
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Novel 3-substituted 8-aza-bicyclo[3.2.1]octanes (commonly known as “tropanes”) substituted in the 8-position are effective as NMDA NR2B antagonists useful for relieving pain.
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- 1,4 substituted piperidinyl NMDA/NR2B antagonists
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Novel piperidinyl compounds substituted in the 1- and 4-positions are effective as NMDA NR2B antagonists useful for relieving pain.
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- An immunotherapeutic program for the treatment of nicotine addiction: Hapten design and synthesis
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People continue to smoke and use tobacco products despite well-established hazardous consequences. The most contributing factor is the addictive nature of nicotine. There is no highly effective treatment for the problem of nicotine dependence. Immunotherapy offers an alternative to conventional approaches. The chemistry necessary for a comprehensive immunopharmacological program is presented. Haptens for the generation of antibodies specific for naturally occurring (S)-nicotine, (S)- and (R)-nornicotine, and the metabolite (S)-cotinine were prepared with high optical purity. Preliminary data for antinicotine antibodies are reported.
- Isomura,Wirsching,Janda
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p. 4115 - 4121
(2007/10/03)
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- Indole derivatives as 5-HT1-like agonists for use in migraine
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The present invention relates to 3,5-disubstituted indole compounds which are selective agonists which act on 5-hdroxytryptamine receptors useful in the treatment of migraine.
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- Reagents and methods for the quantification of imipramine or desipramine in biological fluids
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Immunoassay methods and reagents for the specific quantification of imipramine or desipramine in a test sample are disclosed. The measurement of imipramine or desipramine is accomplished in a specific immunoassay employing antibodies prepared with imipramine or desipramine derivatives of the Formula III: STR1 wherein P is an immunogenic carrier material, X is two heteroatoms, Y is a linking group comprising from 1 to 6 carbon atoms and P is an immunogenic carrier material, and wherein for imipramine, R is CH3, and for desipramine, R is H. The present invention also describes the synthesis of unique labeled reagents of the structure of the Formula IV: STR2 wherein Z is a linking group comprising 1 to 4 carbon atoms and 0 to 2 heteroatoms and Q is a detectable moiety, preferably fluorescein or a fluorescein derivative, and wherein for imipramine, R1 is CH3, and for desipramine, R1 is H.
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- Studies on disease-modifying antirheumatic drugs: Synthesis of novel quinoline and quinazoline derivatives and their anti-inflammatory effect
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In the course of our study aimed at developing new types of DMARDs (disease-modifying antirheumatic drugs), we found that quinoline derivative 1a had a potent anti-inflammatory effect in an adjuvant arthritis (AA) rat model, starting from the potent bone resorption inhibitors justicidins as the lead compounds. Further modification of 1a was performed, and various quinoline and quinazoline derivatives having a heteroaryl moiety on the alkyl side chain at the 2-position of the skeleton were prepared. These compounds were evaluated for antiinflammatory effects using the AA rat model. Most of these compounds, especially those having an imidazole or a triazole moiety on the 2-alkyl chain, exhibited a potent effect. Among the compounds synthesized, ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1- yl-methyl)quinoline-3-carboxylate (12d), having an ED50 value of 2.6 mg/kg/day (anti-inflammatory effect in an AA rat model, po), was selected as a candidate for further investigation. In vitro, 12d inhibited mitogen- induced proliferation at 10-7-10-5 M but not prostaglandin E2 production at 10-5 M. Moreover, 12d preferentially inhibited the IFN-γ production by Th1-type clones over the IL-4 production by Th2-type clones. This preferential suppression of Th1 cytokine production is considered the essential immunomodulating action of 12d for the present. Synthesis and structure-activity relationships for this novel series of quinoline and quinazoline derivatives are detailed.
- Baba, Atsuo,Kawamura, Noriaki,Makino, Haruhiko,Ohta, Yoshikazu,Taketomi, Shigehisa,Sohda, Takashi
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p. 5176 - 5182
(2007/10/03)
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