- Discovery of Orally Bioavailable Purine-Based Inhibitors of the Low-Molecular-Weight Protein Tyrosine Phosphatase
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Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.
- Stanford, Stephanie M.,Diaz, Michael A.,Ardecky, Robert J.,Zou, Jiwen,Roosild, Tarmo,Holmes, Zachary J.,Nguyen, Tiffany P.,Hedrick, Michael P.,Rodiles, Socorro,Guan, April,Grotegut, Stefan,Santelli, Eugenio,Chung, Thomas D. Y.,Jackson, Michael R.,Bottini, Nunzio,Pinkerton, Anthony B.
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p. 5645 - 5653
(2021/05/31)
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- INHIBITORS OF LOW MOLECULAR WEIGHT PROTEIN TYROSINE PHOSPHATASE (LMPTP) AND USES THEREOF
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Protein tyrosine phosphatases (PTPs) are key regulators of metabolism and insulin signaling. As a negative regulator of insulin signaling, the low molecular weight protein tyrosine phosphatase (LMPTP) is a target for insulin resistance and related conditions. Described herein are compounds capable of modulating the level of activity of LMPTP, compositions, and methods of using these compounds and compositions.
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Paragraph 00254
(2019/07/20)
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- Pd(0)/Cu(I)-mediated direct arylation of 2′-deoxyadenosines: Mechanistic role of Cu(I) and reactivity comparisons with related purine nucleosides
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(Chemical Equation Presented) Pd/Cu-mediated direct arylation of 2′-deoxyadenosine with various aryl iodides provides 8-arylated 2′-deoxyadenosine derivatives in good yields. Following significant reaction optimization, it has been determined that a subst
- Storr, Thomas E.,Baumann, Christoph G.,Thatcher, Robert J.,De Ornellas, Sara,Whitwood, Adrian C.,Fairlamb, Ian J. S.
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scheme or table
p. 5810 - 5821
(2009/12/26)
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- Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family
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Adenine derivatives bearing substituents in the 2-, N6-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [3H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N 6-acetyladenine (25, Ki rat: 2.85 μM; Ki human: 0.515 μM) and 8-aminoadenine (33, Ki rat: 6.51 μM; Ki human: 0.0341 μM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family. 2009 American Chemical Society.
- Borrmann, Thomas,Abdelrahman, Aliaa,Volpini, Rosaria,Lambertucci, Catia,Alksnis, Edgars,Gorzalka, Simone,Knospe, Melanie,Schiedel, Anke C.,Cristalli, Gloria,Müller, Christa E.
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supporting information; experimental part
p. 5974 - 5989
(2010/03/24)
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- Aqueous-phase Suzuki-Miyaura cross-coupling reactions of free halopurine bases
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The Suzuki-Miyaura reaction of 9-unsubstituted 2-, 6-, and 8-halopurine bases with diverse aryl- and alkenylboronic acids in water-acetonitrile mixtures under microwave irradiation was used for the single-step synthesis of arylpurines. In most cases the p
- Capek, Petr,Vrabel, Milan,Hasnik, Zbynek,Pohl, Radek,Hocek, Michal
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p. 3515 - 3526
(2008/02/10)
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- Reactions of Benzenediazonium Ions with Adenine and Its Derivatives
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Adenine, adenosine, and 5'-adenylic acid react readily with benzenediazonium ion and its derivatives at pH 8-11 to yield derivatives of (E)-6-(3-phenyl-2-triazen-1-yl)purine.The structural assignments for these compounds, some of which are unstable, are based on their spectroscopic properties and their degradation reactions in acid solution and with sodium dithionite to yield 6-hydrazinopurine.The triazenes decompose in basic aqueous solution at 60-90 deg C to produce 8-aryladenines.For adenosine and 5'-adenylic acid, the ribose residues are cleaved during this process.Several lines of evidence indicate that the triazenes are converted to 8-aryladenines in intermolecular processes.Both the benzenediazonium ion and the phenyl radical can be intercepted during the reaction.Consequently, the phenylation reaction may be confidently formulated as an intermolecular free-radical substitution reaction.
- Chin, Anton,Hung, Ming-Hong,Stock, Leon M.
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p. 2203 - 2207
(2007/10/02)
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