- Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation
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Background and Purpose Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk for stroke, heart failure and cardiovascular-related mortality. Candidate targets for anti-AF drugs include a potassium channel Kv1.5, and the ionic currents I KACh and late INa, along with increased oxidative stress and activation of NFAT-mediated gene transcription. As pharmacological management of AF is currently suboptimal, we have designed and characterized a multifunctional small molecule, compound 1 (C1), to target these ion channels and pathways. Experimental Approach We made whole-cell patch-clamp recordings of recombinant ion channels, human atrial IKur, rat atrial I KACh, cellular recordings of contractility and calcium transient measurements in tsA201 cells, human atrial samples and rat myocytes. We also used a model of inducible AF in dogs. Key Results C1 inhibited human peak and late Kv1.5 currents, frequency-dependently, with IC50 of 0.36 and 0.11 μmol·L-1 respectively. C1 inhibited I KACh (IC50 of 1.9 μmol·L-1) and the Nav1.5 sodium channel current (IC50s of 3 and 1 μmol·L-1 for peak and late components respectively). C1 (1 μmol·L-1) significantly delayed contractile and calcium dysfunction in rat ventricular myocytes treated with 3 nmol·L -1 sea anemone toxin (ATX-II). C1 weakly inhibited the hERG channel and maintained antioxidant and NFAT-inhibitory properties comparable to the parent molecule, resveratrol. In a model of inducible AF in conscious dogs, C1 (1 mg·kg-1) reduced the average and total AF duration. Conclusion and Implications C1 behaved as a promising multifunctional small molecule targeting a number of key pathways involved in AF.
- Baczko, Istvan,Liknes, David,Yang, Wei,Hamming, Kevin C.,Searle, Gavin,Jaeger, Kristian,Husti, Zoltan,Juhasz, Viktor,Klausz, Gergely,Pap, Robert,Saghy, Laszlo,Varro, Andras,Dolinsky, Vernon,Wang, Shaohua,Rauniyar, Vivek,Hall, Dennis,Dyck, Jason R.B.,Light, Peter E.
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Read Online
- A Rh(II)- or Ag(I)-Catalyzed Formal C-O Bond Insertion of Cyclic Hemiaminal with Aryl Diazoacetate
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A mild and facile synthetic method via convergent assembly of two reactive intermediates generated in situ has been developed. This method provides an efficient way to construct six- and sevenmembered N-heterocycles containing a biaryl linkage. This react
- Xu, Cong,Liu, Xiangrong,Xie, Xiongda,Deng, Lin,Xu, Xinfang,Chan, Albert S. C.,Hu, Wenhao
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supporting information
p. 1957 - 1962
(2021/09/22)
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- Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone
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Highly substituted fluorenones are readily prepared in mostly fair to good yields via metal- and additive-free TBHP-promoted cross-dehydrogenative coupling (CDC) of readily accessible N-methyl-2-(aminomethyl)biphenyls and 2-(aminomethyl)biphenyls. This methodology is compatible with numerous functional groups (methoxy, cyano, nitro, chloro, and SEM and TBS-protective groups for phenols) and was further utilized in the first total synthesis of the natural product nobilone.
- Bracher, Franz,Jourjine, Ilya A. P.,Krau?, Jürgen,Zeisel, Lukas
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supporting information
p. 2668 - 2679
(2021/11/30)
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- First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate
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Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitor
- Cinelli, Maris A.,Reidl, Cory T.,Li, Huiying,Chreifi, Georges,Poulos, Thomas L.,Silverman, Richard B.
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p. 4528 - 4554
(2020/05/05)
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- Enantioselective Reductive Coupling of Imines Templated by Chiral Diboron
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We herein report a general, practical, and highly efficient method for asymmetric synthesis of a wide range of chiral vicinal diamines via reductive coupling of imines templated by chiral diboron. The protocol features high enantioselectivity and stereospecificity, mild reaction conditions, simple operating procedures, use of readily available starting materials, and a broad substrate scope. The method signifies the generality of diboron-enabled [3,3]-sigmatropic rearrangement.
- Chen, Dongping,Li, Kaidi,Tang, Wenjun,Xu, Guangqing,Xu, Ronghua,Zhou, Mingkang
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supporting information
p. 10337 - 10342
(2020/07/04)
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- Asymmetric Hydrogenation of Dibenzo[ c,e]azepine Derivatives with Chiral Cationic Ruthenium Diamine Catalysts
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An efficient Ru-catalyzed asymmetric hydrogenation of dibenzo[c,e]azepines is reported. A series of seven-membered cyclic amines were obtained with moderate to excellent enantioselectivity. The catalyst counteranion played an important role in achieving high-level chiral induction. Moreover, a one-pot synthesis of chiral 6,7-dihydro-5H-dibenz[c,e]azepines via two-step reductive amination was also developed.
- Zhang, Shanshan,Chen, Fei,He, Yan-Mei,Fan, Qing-Hua
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supporting information
p. 5538 - 5541
(2019/08/01)
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- Palladium-Catalyzed α-Arylation of Silylenol Ethers in the Synthesis of Isoquinolines and Phenanthridines
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A diverse array of isoquinolines and phenanthridines have been accessed by developing a two-step, one-pot method constituting regioselective palladium-catalyzed Kuwajima-Urabe α-arylation of silylenol ethers and acid-mediated deprotection, annulation, and aromatization. Structural diversity in the silylenol ethers leads to three different classes of isoquinolines and phenanthridines from which related natural products can be derived. The synthetic utility of this method by the quick assembly of the natural product trispheridine is also demonstrated.
- Saini, Gaurav,Kumar, Pravin,Kumar, Gangam Srikanth,Mangadan, Arun Raj Kizhakkayil,Kapur, Manmohan
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p. 441 - 444
(2018/01/28)
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- Aminolithiation–arylation consecutive cyclization of N-(2-fluorophenyl)methylaminoalkylstyryls giving aryl-substituted pyrido[1,2-b]isoquinolines
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Aminolithiation–arylation tandem cyclization of N-(2-fluorophenyl)methylaminoalkylstyryls proceeded smoothly to give hexahydro-2H-pyrido[1,2-b]isoquinoline using a stoichiometric amount of n-BuLi with high trans selectivity. The arylation reaction was highly accelerated by the addition of HMPA. Both pyrido- and pyrrolo-[1,2-b]isoquinoline were successfully constructed by this tandem reaction.
- Yamamoto, Yasutomo,Nakanishi, Yasue,Yamada, Ken-ichi,Tomioka, Kiyoshi
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supporting information
p. 5309 - 5318
(2018/06/11)
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- 2-METHYL-QUINAZOLINES
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The present invention describes 2-methyl-quinazoline compounds of general formula (I), methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions. The 2-methyl substituted quinazoline compounds of general formula(I) effectively and selectively inhibit the Ras-Sos interaction without significantly targeting the EGFR receptor. They are therefore useful for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, such as cancer as a sole agent or in combination with other active ingredients.
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(2018/10/19)
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- REMOTE HETEROARYL ALKENYLATION WITH CATALYTIC BIFUNCTIONAL TEMPLATE
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We report the design of a catalytic, bifunctional template that binds heterocyclic substrate via reversible coordination instead of covalent linkage, allowing remote site- selective C-H olefination of heterocycles. The two metal centers coordinated to this template play different roles; anchoring substrates to the proximity of catalyst and cleaving the remote C-H bonds respectively. Using this strategy, we demonstrate remote site-selective C-H olefination of heterocyclic substrates which do not have functional group handles for covalently attaching templates. For instance the olefination can be an alkenylation of a 3- phenylpyridine with an acrylate alkyl ester selective for the meta position of the phenyl group with respect to the pyridine, or can be an alkenylation of a quinoline with an acrylate alkyl ester selective for the 5-position of the quinoline.
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(2018/09/18)
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- RESVERATROL ANALOGS AND THERAPEUTIC USES THEREOF
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Resveratrol analogs and their use to inhibit Kv1.5 channels are provided. The resveratrol analogs are useful in the treatment of atrial arrhythmias, including atrial fibrillation (AF). Exemplary resveratrol analogs are compounds of general Formula (I):
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Paragraph 00167
(2014/12/12)
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- CHEMICAL COMPOUNDS
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The invention is directed to substituted heteroaryl derivatives. Specifically, the invention is directed to compounds according to Formula Q: wherein D, L, M, W, X, Y, and Z are defined herein. The compounds of the invention are inhibitors of DNA methyltransferase (DNMT) activity - including DNMT1, DNMT3a, or DNMT3b- and are useful in the treatment of cancer and hyperproliferative diseases. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention
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Page/Page column 131
(2013/05/21)
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- Light emitting materials for Electronics
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The present invention relates to an organometallic complex, to the preparation of said material, to the use of said material and to a light emitting device which transform electric energy into light. The present invention is further related to provide phosphorescent complexes which contribute to extend the life time in operation of said OLEDs and especially when they are involved in the EL. The objectives of this invention are accomplished by iridium complex comprising 7-membered fused ring ligands which are tris-homoleptic or bis-homoleptic with an ancillary ligand.
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Page/Page column 26
(2012/03/26)
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- LIGHT EMITTING MATERIALS FOR ELECTRONICS
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The present invention relates to an organometallic complex, to the preparation of said material, to the use of said material and to a light emitting device which transform electric energy into light. The present invention is further related to provide phosphorescent complexes which contribute to extend the life time in operation of said OLEDs and especially when they are involved in the EL. The objectives of this invention are accomplished by iridium complex comprising 7-membered fused ring ligands which are tris-homoleptic or bis-homoleptic with an ancillary ligand.
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Page/Page column 33-34
(2012/03/09)
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- Thermal cyclization of nonconjugated aryl-yne-carbodiimide furnishing a dibenzonaphthyridine derivative
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The reagent-free C2-C7 thermal cyclization of a nonconjugated aryl-yne-carbodiimide yielded a dibenzo- [b,g][1,8]naphthyridine derivative, whose congeners are known to possess fascinating pharmacological properties. This is the first heteroaromatic compound prepared by the thermal cycloaromatization of "nonconjugated" aryl-ynes.
- Kimura, Hidenori,Torikai, Kohei,Ueda, Ikuo
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experimental part
p. 393 - 396
(2009/12/25)
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- Synthesis and structure-activity relationships of novel dipeptides and reduced dipeptides as ligands for melanocortin subtype-4 receptor
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A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-d-Tic-d-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.
- Shi, Qing,Ornstein, Paul L.,Briner, Karin,Richardson, Timothy I.,Arnold, Macklin B.,Backer, Ryan T.,Buckmaster, Jennifer L.,Canada, Emily J.,Doecke, Christopher W.,Hertel, Larry W.,Honigschmidt, Nick,Hsiung, Hansen M.,Husain, Saba,Kuklish, Steve L.,Martinelli, Michael J.,Mullaney, Jeffrey T.,O'Brien, Thomas P.,Reinhard, Matt R.,Rothhaar, Roger,Shah, Jikesh,Wu, Zhipei,Xie, Chaoyu,Zgombick, John M.,Fisher, Matthew J.
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p. 2341 - 2346
(2007/10/03)
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- Fused tricyclic compounds as inhibitors of 17beta-hydroxysteroid dehydrogenase 3
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Fused tricyclic compounds, methods of using such compounds in the treatment of hormone sensitive diseases such as prostate cancer, and pharmaceutical compositions containing such compounds.
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Page/Page column 62
(2010/02/14)
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- Sulfonamide derivatives for the treatment of diseases
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The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in
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Page/Page column 32
(2008/06/13)
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- CARBOXYLIC ACID DERIVATIVE AND MEDICINE COMPRISING SALT OR ESTER OF THE SAME
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The present invention provides novel carboxylic acid derivatives useful as an insulin sensitizer, a salt thereof or a hydrate of them, and a medicament comprising the derivative as the active ingredient. Specifically, it provides a carboxylic acid derivative represented by the following formula: (wherein L represents a single bond, or a C1 to C6 alkylene group, a C2 to C6 alkenylene group or a C2 to C6 alkynylene group, each of which may have one or more substituent groups; M represents a single bond, or a C1 to C6 alkylene group, a C2 to C6 alkenylene group or a C2 to C6 alkynylene group, each of which may have one or more substituent groups; T represents a single bond, or a C1 to C3 alkylene group, a C2 to C3 alkenylene group or a C2 to C3 alkynylene group, each of which may have one or more substituent groups; W represents a carboxyl group; X represents a single bond, an oxygen atom, or a group represented by the various substituent groups including -NRX1CQ1O- (wherein Q1 represents an oxygen atom or a sulfur atom; RX1 represents a hydrogen atom, a cyano group, a formyl group, or various groups including a C1 to C6 alkyl group and a C1 to C6 hydroxyalkyl group, each of which may have one or more substituent groups) , ONRX1CQ1-, -NRX1CQ1-, -CQ1NRX1-, -NRX1aCQ1NRX1b-, -Q2SO2- and -SO2Q2-; Y represents a 5 to 14-membered aromatic group which may have one or more substituent groups and one or more hetero atoms, or a C3 to C7 alicyclic hydrocarbon group; and the rings Z and U may be the same as or different from each other and each represents a 5 to 14-membered aromatic group which may have 1 to 4 substituent groups and one or more hetero atoms, and the ring may be partially saturated.), a salt thereof, an ester thereof or a hydrate of them.
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- Piperazine- and piperidine-derivatives as melanocortin receptor agonists
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The present invention relates to melanocortin receptor agonists of formula I, which is useful in the treatment of obesity, diabetes and male and/or female sexual dysfunction.
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Page/Page column 52
(2010/02/06)
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and treating blood coagulation and cardiovascular disorders and have the following structure: wherein R3 is hydrogen or halogen, and u is N or CH.
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- Naphtho-fused lactams promote release of growth hormone
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The present invention is directed to certain naphtho-fused lactams of the general structural formula: wherein and R1, R1a, R1b, R2a, R2b, R3a, R4, R5, R6, A, L, X, n, p and w are as defined herein. These compounds promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, such as short stature in growth hormone deficient children, and to treat medical conditions which are improved by the anabolic effects of growth hormone.
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- A potent, orally bioavailable benzazepinone growth hormone secretagogue
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The identification of L-739,9.43 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L- 692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the ne
- DeVita, Robert J.,Bochis, Richard,Frontier, Alison J.,Kotliar, Andrew,Fisher, Michael H.,Schoen, William R.,Wyvratt, Matthew J.,Cheng, Kang,Chan, Wanda W.-S.,Butler, Bridget,Jacks, Thomas M.,Hickey, Gerard J.,Schleim, Klaus D.,Leung, Kwan,Chen, Zhesheng,Lee Chiu,Feeney, William P.,Cunningham, Paul K.,Smith, Roy G.
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p. 1716 - 1728
(2007/10/03)
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- Benzo-fused lactams promote release of growth hormone
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There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient therefore are also disclosed.
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- Benzo-Fused Lactams promote release of growth hormone
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There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.
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- Benzo-fused lactams promote release of growth hormone
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There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. The compounds are prepared by substitution of an amino-lactam with a substituted amide function. Growth promoting compositions containing such bezno-fused lactams as the active ingredient thereof are also disclosed. STR1 where L is STR2
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- Benzo-fused macrocycles promote release of growth hormone
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There are disclosed certain novel compounds identified as benzo-fused macrocycles which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused macrocycles as the active ingredient thereof are also disclosed.
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