- SELECTIVE HDAC1,2 INHIBITORS
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Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases or disorders associated with HDAC1 and/or HDAC2 activity.
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- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR
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The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.
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Paragraph 0607-0608
(2018/04/20)
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- CEREBLON LIGANDS AND BIFUNCTIONAL COMPOUNDS COMPRISING THE SAME
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The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Paragraph 0641; 0642; 0643; 0644; 0645
(2018/08/20)
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- Mechanisms of action of novel influenza A/M2 viroporin inhibitors derived from hexamethylene amiloride
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The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)'derived compounds that inhibit the wildtype and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotinamide (9) inhibits amantadine-sensitive M2 currents with 3- to 6-fold greater potency than amantadine or HMA (IC50 5 0.2 vs. 0.6 and 1.3 μM, respectively). Compound 9 competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9 binds at site(s) that overlap with amantadine binding. In addition, tert-butyl 4′-(carbamimidoylcarbamoyl)-2′,3-dinitro- [1,1′-biphenyl]-4-carboxylate (27) acts both on adamantanesensitive and a resistantM2variant encoding a serine to asparagine 31 mutation (S31N) with improved efficacy over amantadine and HMA (IC5050.6 μMand4.4mM, respectively).Whereas 9 inhibited in vitro replication of influenza virus encoding wild-type M2 (EC505 2.3 μM), both 27 and tert-butyl 4′-(carbamimidoylcarbamoyl)-2′,3- dinitro-[1,1′-biphenyl]-4-carboxylate (26) preferentially inhibited viruses encoding M2(S31N) (respective EC50 5 18.0 and 1.5 μM). This finding indicates thatHMAderivatives can be designed to inhibit viruses with resistance to amantadine. Our study highlights the potential of HMA derivatives as inhibitors of drug-resistant influenza M2 ion channels.
- Jalily, Pouria H.,Eldstrom, Jodene,Miller, Scott C.,Kwan, Daniel C.,Tai, Sheldon S.-H.,Chou, Doug,Niikura, Masahiro,Tietjen, Ian,Fedida, David
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supporting information
p. 80 - 95
(2016/07/28)
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- GLYCINE COMPOUND
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[Problem] The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. [Means for Solution] The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that a compound of the present invention or a salt thereof exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. The present invention further relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound of the present invention or a salt thereof, and an excipient.
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Page/Page column 20
(2012/07/28)
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- TROPANE COMPOUNDS
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A compound according to Formula I or II: (I) or (II) wherein R1, R1b, R2, L1, and L2 and L2b are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 374-375
(2009/05/30)
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- Novel CXCR3 antagonists with a piperazinyl-piperidine core
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High-throughput screening of an encoded combinatorial aryl piperazine library led to the identification of a novel series of potent piperazinyl-piperidine based CXCR3 antagonists. Analogs of the initial hit were synthesized via solid and solution phase me
- McGuinness, Brian F.,Carroll, Carolyn DiIanni,Zawacki, Lisa Guise,Dong, Guizhen,Yang, Cangming,Hobbs, Doug W.,Jacob-Samuel, Biji,Hall III, James W.,Jenh, Chung-Her,Kozlowski, Joseph A.,Anilkumar, Gopinadhan N.,Rosenblum, Stuart B.
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body text
p. 5205 - 5208
(2010/03/31)
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