- Synthesis and Optimization of Kv7 (KCNQ) Potassium Channel Agonists: The Role of Fluorines in Potency and Selectivity
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Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysiology platform in HEK293 cells but lack activity on Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5, resulting in a selectivity index SI > 10. RL-56 is remarkably potent, EC2x 0.11 ± 0.02 μM, and still shows an SI = 2.5. We also identified analogues with significant selectivity for Kv7.4/Kv7.5 over Kv7.2/Kv7.3. The extensive use of fluorine in iterative core structure modifications highlights the versatility of these substituents, including F, CF3, and SF5, to span orders of magnitude of potency and selectivity in medicinal chemistry lead optimizations.
- Liu, Ruiting,Tzounopoulos, Thanos,Wipf, Peter
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supporting information
p. 929 - 935
(2019/06/13)
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- SELECTIVE POTASSIUM CHANNEL AGONISTS
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Selective potassium channel agonists and methods of use thereof are disclosed. A compound, or a pharmaceutically acceptable salt thereof, having a formula (I) wherein R1 is H or optionally-substituted alkyl; R2 is optionally-substituted C1-C6 alkyl or optionally- substituted cyclopropyl; R3 and R4 are each independently H or optionally- substituted alkyl; R5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R6 and R7 are each independently H, optionally- substituted alkyl, or R6 and R7 together form a carbocycle; R8 is substituted phenyl or optionally-substituted pyridinyl, provided that if R8 is substituted phenyl, then R2 is optionally-substituted cyclopropyl; and R9, R10 and R11 are each independently H, halo, or optionally- substituted alkyl.
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Page/Page column 45
(2019/11/12)
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- Continuous flow synthesis of difluoroamine systems by direct fluorination
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Continuous flow methodology for the synthesis of perfluoroaryl difluoroamine derivatives by reaction of fluorine gas with an appropriate perfluoroaniline substrate is described, further demonstrating the efficient use of flow regimes for reactions involvi
- McPake, Christopher B.,Murray, Christopher B.,Sandford, Graham
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p. 145 - 150
(2013/04/10)
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- 2-(4,5,6,7-Tetrafluorobenzimidazol-2-yl)-4,4,5,5-tetramethyl-4,5-dihydro-1- H-imidazole-3-oxide-1-oxyl, a hydrogen-bonded organic quasi-1D ferromagnet
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The title radical (F4BImNN) is a stable nitronylnitroxide that forms hydrogen-bonded NH?ON chains in the solid state. The chains assemble the F4BImNN molecules to form stacked contacts between the radical groups, in a geometry that is expected to exhibit
- Murata, Hidenori,Miyazaki, Yuji,Inaba, Akira,Paduan-Filho, Armando,Bindilatti, Valdir,Oliveira Jr., Nei Fernandes,Delen, Zeynep,Lahti, Paul M.
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p. 186 - 194
(2008/09/21)
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- CHARGE-TRANSPORT MATERIALS, METHODS OF FABRICATION THEREOF, AND METHODS OF USE THEREOF
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Briefly described, embodiments of this disclosure include charge-transport materials, methods of forming charge-transport materials, and methods of using the charge-transport materials.
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Page/Page column 119
(2008/06/13)
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- Cancer treatment
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This invention is a method of treating cancer, including carcinomas and sarcomas through the administration of a pharmaceutical composition containing a tetra-substituted benzimidazole carbamate. The tetra-substituted benzimidazole carbamate is selected f
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- Polyhalogenonitrobenzenes and derived compounds: Part 5. Improved preparations of 1,2,3,4-tetrafluoro-5,6-dinitrobenzene and 3,4,5,6-tetrafluoro-1,2-phenylenediamine, and the use of the latter for the synthesis of tetrafluorobenzheterocycles
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The preparation of 2,3,4,5-tetrafluoro-6-nitroaniline (3) by amination of pentafluoronitrobenzene has been speeded up, scaled up and the yield increased by controlling the reaction by TLC monitoring and using 'dry column' chromatography. Compound (3) was readily converted to 1,2,3,4-tetrafluoro-5,6-dinitrobenzene (2) by peroxytrifluoroacetic acid and to 3,4,5,6-tetrafluoro-1,2-phenylenediamine (1) by SnCl2/HCl, Compound (1) was shown to be a versatile intermediate for the synthesis of tetrafluoro-benzimidazoles, -triazoles and -quinoxalines. The fungicidal activity of the latter are reported here.
- Heaton, Alan,Hill, Mark,Drakesmith, Frederick
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p. 133 - 138
(2007/10/03)
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- Glycine receptor antagonists and the use thereof
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Methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions, inducing anesthesia and treating psychosis are disclosed by administering to an animal in need of such treatment a compound having high affinity for the glycine binding site, lacking PCP side effects and which crosses the blood brain barrier of the animal. Also disclosed are novel 1,4-dihydroquinoxaline-2,3-diones, and pharmaceutical compositions thereof. Also disclosed are highly soluble ammonium salts of 1,4-dihydroquinoxaline-2,3-diones.
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- REACTION OF AROMATIC COMPOUNDS WITH NUCLEOPHILIC REAGENTS IN LIQUID AMMONIA. X. AMINATION OF POLYFLUORINATED AROMATIC COMPOUNDS CONTAINING ELECTRON-WITHDRAWING SUBSTITUENTS
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It was shown for the case of 2,4-difluoro-, 2,4,6-trifluoro-, and pentafluoronitrobenzenes that both liquid ammonia and sodium amide in liquid ammonia are effective reagents for aminodefluorination with respect to the fluorine derivatives of nitrobenzene.The observed tendency for the ortho-orientation with respect to the nitro group to change to para-orientation with increase in the number of fluorine atoms is more clearly defined for sodium amide than for liquid ammonia as nucleophile on account, clearly, of the stabilization of the transition state of ortho-substitution in the latter case by an intramolcular hydrogen bond.
- Selivanova, G. A.,Chuikova, T. V.,Shtark, A. A.,Shteingarts, V. D.
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p. 2267 - 2272
(2007/10/02)
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