- Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic μ-Opioid Receptor (MOR) Agonist/δ-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability
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We have previously reported a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in mice, and do not produce dependence. Although these attributes are promising, these analogues exhibit poor metabolic stability in mouse liver microsomes, likely due to the central tetrahydroquinoline scaffold in this series. As such, a structure-activity relationship (SAR) campaign was pursued to improve their metabolic stability. This resulted in a shift from our original bicyclic tetrahydroquinoline core to a monocyclic benzylic-core system. By eliminating one of the rings in this scaffold and exploring the SAR of this new core, two promising analogues were discovered. These analogues (5l and 5m) had potency and efficacy values at MOR better or comparable to morphine, retained their DOR-antagonist properties, and showed a 10-fold improvement in metabolic stability.
- Henry, Sean P.,Fernandez, Thomas J.,Anand, Jessica P.,Griggs, Nicholas W.,Traynor, John R.,Mosberg, Henry I.
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p. 4142 - 4157
(2019/05/06)
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- Design, synthesis and biological evaluation of novel ring-opened cromakalim analogues with relaxant effects on vascular and respiratory smooth muscles and as stimulators of elastin synthesis
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Two new series of ring-opened analogues of cromakalim bearing sulfonylurea moieties (series A: with N-unmethylated sulfonylureas, series B: with N-methylated sulfonylureas) were synthesized and tested as relaxants of vascular and respiratory smooth muscle
- Bouhedja, Mourad,Peres, Basile,Fhayli, Wassim,Ghandour, Zeinab,Boumendjel, Ahcène,Faury, Gilles,Khelili, Smail
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p. 774 - 796
(2018/01/05)
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- Synthesis of Spirofurooxindoles via Phenyliodine(III) Bis(trifluoroacetate) (PIFA)-Mediated Cascade Oxidative C?O and C?C Bond Formation
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Upon treatment with solely a hypervalent iodine reagent of phenyliodine(III) bis(trifluoroacetate) (PIFA), 3-(2-hydroxyphenyl)-3-oxo-N-phenyl propanamides and a series of its derivatives were conveniently converted to a class of undocumented spirofurooxindoles under mild conditions. Control experiments provided evidence that this spirocyclization process encompassed a cascade oxidative reactions involving the formation of a C?O bond prior to that of C?C bond. (Figure presented.).
- Sun, Desong,Zhao, Xiaoyuan,Zhang, Bobo,Cong, Ying,Wan, Xintong,Bao, Mingmai,Zhao, Xue,Li, Bing,Zhang-Negrerie, Daisy,Du, Yunfei
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supporting information
p. 1634 - 1638
(2018/03/21)
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- Mechanistic study on iodine-catalyzed aromatic bromination of aryl ethers by N-Bromosuccinimide
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Although iodine-catalyzed reaction has rapid advances in recent years, examples on iodine-catalyzed bromination are rare and the mechanism of these reactions remains unclear. Herein, we reported an I2-catalyzed aromatic bromination of aryl ethers by NBS and presented the details of the mechanistic study including kinetic study and the study of kinetic isotope effects. The study revealed that the reaction was actually catalyzed by IBr formed in the induction period, and the rate-determining step was the HBr-elimination of the Wheland intermediate assisted by IBr.
- Pramanick, Pranab Kumar,Hou, Zhen-Lin,Yao, Bo
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p. 7105 - 7114
(2017/11/27)
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- LYSYL OXIDASE-LIKE 2 INHIBITORS AND USES THEREOF
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Described herein are compounds that are LOXL2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with LOXL2 activity.
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Paragraph 00255
(2017/02/24)
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- Direct Transformation of Ethylarenes into Primary Aromatic Amides with N -Bromosuccinimide and I2-Aqueous NH3
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A variety of ethylarenes were converted into the corresponding primary aromatic amides in good yields via treatment with N-bromosuccinimide in the presence of a catalytic amount of 2,2′-azobis(isobutyronitrile) in a mixture of ethyl acetate and water, acetonitrile and water, or chloroform and water, followed by reaction with molecular iodine and aq NH3 in one pot. It was found that aryl α-bromomethyl ketones and/or aryl methyl ketones were formed at the first reaction step and their iodoform-type reaction occurred at the second reaction step to provide primary aromatic amides. The present reaction is a useful and practical transition-metal-free method for the preparation of primary aromatic amides from ethylarenes. (Chemical Equation Presented).
- Shimokawa, Shohei,Kawagoe, Yuhsuke,Moriyama, Katsuhiko,Togo, Hideo
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supporting information
p. 784 - 787
(2016/03/01)
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- Iridium-Catalyzed Intramolecular Methoxy C?H Addition to Carbon–Carbon Triple Bonds: Direct Synthesis of 3-Substituted Benzofurans from o-Methoxyphenylalkynes
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Catalytic hydroalkylation of an alkyne with methyl ether was accomplished. Intramolecular addition of the C?H bond of a methoxy group in 1-methoxy-2-(arylethynyl)benzenes across a carbon–carbon triple bond took place efficiently either in toluene at 110 °C or in p-xylene at 135 °C in the presence of an iridium catalyst. The initial 5-exo cyclization products underwent double-bond migration during the reaction to give 3-(arylmethyl)benzofurans in high yields.
- Torigoe, Takeru,Ohmura, Toshimichi,Suginome, Michinori
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supporting information
p. 10415 - 10419
(2016/07/21)
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- Pyrrole inhibitors of S-nitrosoglutathione reductase as therapeutic agents
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The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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Page/Page column 312-313
(2015/11/16)
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- Pyrazolyl-Based Carboxamides I
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The invention relates to pyrazolyl-based carboxamide compounds useful as ICRAC inhibitors, to pharmaceutical compositions containing these compounds and to these compounds for the use in the treatment and/or prophylaxis of diseases and/or disorders, in particular inflammatory diseases and/or inflammatory disorders.
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Paragraph 0427-0429
(2014/07/22)
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- PYRAZOLYL-BASED CARBOXAMIDES I AS CRAC CHANNEL INHIBITORS
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The Invention relates to pyrazolyl-based carboxamide compounds of formula (l) useful as ICRAC inhibitors, to pharmaceutical compositions containing these compounds and to these compounds for the use in the treatment and/or prophylaxis of diseases and/or disorders, in particular inflammatory diseases and/or inflammatory disorders.
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Page/Page column 56; 57
(2014/07/23)
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- Fast and efficient bromination of aromatic compounds with ammonium bromide and Oxone
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A highly efficient, rapid and regioselective protocol was developed for the ring bromination of aromatic compounds under mild conditions with ammonium bromide as a source of bromine source and Oxone (potassium peroxysulfate) as an oxidant. No metal catalyst or acidic additive is required. A variety of aromatic compounds, including methoxy, hydroxy, amino, and alkyl arenes, reacted smoothly to give the corresponding monobrominated products in good to excellent yields in very short reaction times. Moreover, dibromination of deactivated anilines to give the corresponding dibromides proceeded in high yields. Interestingly, 1-(2-naphthyl)ethanone provided a ring-brominated product. Georg Thieme Verlag Stuttgart . New York.
- Naresh, Mameda,Arun Kumar, Macharla,Mahender Reddy, Marri,Swamy, Peraka,Nanubolu, Jagadeesh Babu,Narender, Nama
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p. 1497 - 1504
(2013/06/27)
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- Acetylenic linkers in lead compounds: A study of the stability of the propargyl-linked antifolates
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Propargyl-linked antifolates that target dihydrofolate reductase are potent inhibitors of several species of pathogenic bacteria and fungi. This novel class of antifolates possesses a relatively uncommon acetylenic linker designed to span a narrow passage in the enzyme active site and join two larger functional domains. Because the use of alkyne functionality in drug molecules is limited, it was important to evaluate some key physicochemical properties of these molecules and specifically to assess the overall stability of the acetylene. Herein, we report studies on four compounds from our lead series that vary specifically in the environment of the alkyne. We show that the compounds are soluble, chemically stable in water, as well as simulated gastric and intestinal fluids with half-lives of approximately 30 min after incubation with mouse liver microsomes. Their primary in vitro route of metabolism involves oxidative transformations of pendant functionality with little direct alteration of the alkyne. Identification of several major metabolites indicated the formation of N-oxides; the rate of formation of these oxides was highly influenced by branching substitutions around the propargyl linker. On the basis of the lessons of these metabolic studies, a more advanced inhibitor was designed, synthesized, and shown to have increased (t1/2 = 65 min) metabolic stability while maintaining potent enzyme inhibition. Copyright
- Zhou, Wangda,Viswanathan, Kishore,Hill, Dennis,Anderson, Amy C.,Wright, Dennis L.
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p. 2002 - 2008,7
(2020/08/24)
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- Directed regioselectivity of bromination of ketones with NBS: solvent-free conditions versus water
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The reaction conditions employed directed the site of functionalisation of ketones with NBS: under solvent-free conditions α-bromination was the exclusive process, while in water, ring functionalisation occurred in the case of methoxy substituted aromatic ketones.
- Pravst, Igor,Zupan, Marko,Stavber, Stojan
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p. 4707 - 4710
(2007/10/03)
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- Model studies towards the synthesis of gilvocarcin M
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In model studies towards the synthesis of gilvocarcin M, a convergent, xanthate-based free-radical strategy was tested in order to construct the key aromatic ring attached to the sugar unit. The Royal Society of Chemistry 2005.
- Cordera-Vargas, Alejandro,Quiclet-Sire, Beatrice,Zard, Samir Z.
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p. 4432 - 4443
(2007/10/03)
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- Formylchromone derivatives as a novel class of protein tyrosine phosphatase 1B inhibitors
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Formylchromone inhibits a human protein tyrosine phosphatase PTP1B with a IC50 value of 73 μM. The chemical reactivity of formylchromone was adjusted by substitution at various positions of the formylchromone skeleton. In an initial assessment of the structure-activity relationship, the most potent inhibitor showed an IC50 of 4.3 μM against PTP1B and strong or medium selectivity against other human PTPases, LAR and TC-PTP. This compound, however, was not selective against microbial PTPases, YPTP1 and YOP. The potency and selectivity of the formylchromone derivatives expecting further improvements provides a novel pharmacophore for the design of drugs for the treatmenrt of type 2 diabetes and obesity.
- Shim, Yi Sup,Kim, Ki Chul,Chi, Dae Yoon,Lee, Keun-Hyeung,Cho, Hyeongjin
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p. 2561 - 2563
(2007/10/03)
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- Inhibitors of protein kinase for the treatment of disease
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The present invention is directed in part towards methods of modulating the function of protein kinases with phenol- and hydroxynaphthalene-based compounds. The methods incorporate cells that express a protein kinase. In addition, the invention describes methods of preventing and treating protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to phenol- and hydroxynaphthalene-based compounds and pharmaceutical compositions comprising these compounds.
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- Regiocontrolled synthesis of the macrocyclic polyamine alkaloid (±)-lunarine, a time-dependent inhibitor of trypanothione reductase
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A regiocontrolled synthesis of the macrocyclic polyamine alkaloid (±)-lunarine is described. The key steps involve the preparation of the differentially functionalised cis-3-oxo-8-bromo-9b-cyano-1,2,3,4,4a,9b-hexahydrobenzofuranyl tricyclic scaffold 14 wh
- Hamilton, Chris J.,Fairlamb, Alan H.,Eggleston, Ian M.
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p. 1115 - 1123
(2007/10/03)
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- Optically active C3-symmetric triarylphosphines in asymmetric allylations
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A new class of optically active, monodentate, C3-symmetric ligands for asymmetric catalysis, 1-3, were prepared via routes involving asymmetric reduction of aryl ketones (Schemes 1-3). Single crystal X-ray structures of trans-PdCl2(phosphine)2 complexes of ligands 1a, 2a and 3a showed that the ligands do not adopt perfect C3-symmetric conformations in the solid state; in fact, all three have one aromatic ring lying 'face-on' to the metal. Circular dichroism studies of the same complexes provided some evidence for an aromatic ordering effect for complex 22, but none for 21 and 23. Palladium catalyzed allylation reactions using ligands 1-3 showed that encouraging enantioselectivities could be obtained, particularly for cyclic, allylic substrates.
- Powell, Mark T.,Porte, Alexander M.,Reibenspies, Joe,Burgess, Kevin
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p. 5027 - 5038
(2007/10/03)
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- Trisubstituted phenyl derivatives having retinoid agonist, antagonist or inverse agonist type biological activity
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Compounds of the formula where the symbols have the meaning defined in the specification, have retinoid, retinois antagonist or retinoid inverse agonist type biological activity.
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- Halogenation of Phenols and Phenyl Ethers with Potassium Halides in the Presence of 18-Crown-6 on Oxidation with m-Chloroperbenzoic Acid
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Several types of phenyl ethers have been monobrominated in the ring in good yields with potassium bromide in the presence of 18-crown-6 on oxidation with m-chloroperbenzoic acid.Monoiodination takes place with both phenyl ethers and free phenols when potassium iodide is employed.
- Srebnik, Morris,Mechoulam, Raphael,Yona, Irene
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p. 1423 - 1428
(2007/10/02)
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