- 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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- Preparation method of 2-aminomethyl-5-trifluoromethylpyridinium salt
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The invention discloses a preparation method of 2-aminomethyl-5-trifluoromethylpyridinium salt, and belongs to the technical field of pesticides and medical intermediates. According to the method, 2-cyano-3-chloro-5-trifluoromethylpyridine is taken as a raw material, hydrogenation is carried out in an alcohol solvent and an acid in the presence of a metal catalyst, molecular dechlorination is carried out while nitrile group hydrogenation is carried out, and the product 2-aminomethyl-5-trifluoromethylpyridinium salt is obtained after treatment. The method has the advantages of reasonable technical route selection, short reaction steps, mild reaction conditions, low raw material cost and high separation yield, and is suitable for industrial amplification.
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Paragraph 0045-0046
(2020/06/17)
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- Carbamate compounds
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Carbamate compounds having a structure represented by formula I (where R1, R2, R3, R4, R5 and R6 are as defined herein) are useful as anti-tumor agents.
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Page/Page column 18
(2008/12/08)
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- Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
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Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity, wherein X1, X2, X3, X4, X5, R5, R6, R7, R8a, R8b, R9, Z1, Z2 and L are as defined in the description.
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- Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
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Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity.
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Page/Page column 68
(2010/02/11)
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- Novel process for the preparation of 2-aminomethylpyridine derivative
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Process for the preparation of 2-aminomethylpyridine derivative of general formula (I) or a salt thereof : ???in which :n represents 0, 1, 2 or 3,X is halogen atom,each Y may be the same or different and may be a halogen atom, a halogenoalkyl, an alkoxycarbonyl or an alkylsulphonyl.
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Page column 3
(2008/06/13)
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- Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
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Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity.
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