39620-02-5Relevant articles and documents
Developing dual functional allosteric modulators of GABAA receptors
Liu, Xiaodong F.,Chang, Hui-Fang,Schmiesing, Richard Jon,Wesolowski, Steven S.,Knappenberger, Katharine S.,Arriza, Jeffrey L.,Chapdelaine, Marc J.
, p. 8374 - 8382 (2010)
Positive modulators at benzodiazepine sites of α2- and α3-containing GABAA receptors are believed to be anxiolytic. Negative allosteric modulators of α5-containing GABAA receptors enhance cognition. By oocyte two-electrode voltage clamp and subsequent structure-activity relationship studies, we discovered cinnoline and quinoline derivatives that were both positive modulators at α2-/α3-containing GABAA receptors and negative modulators at α5-containing GABAA receptors. In addition, these compounds showed no functional activity at α1-containing GABAA receptors. Such dual functional modulators of GABAA receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses.
From ergolines to indoles: Improved inhibitors of the human H3 receptor for the treatment of narcolepsy
Auberson, Yves P.,Troxler, Thomas,Zhang, Xuechun,Yang, Charles R.,Feuerbach, Dominik,Liu, Yu-Chih,Lagu, Bharat,Perrone, Mark,Lei, Lijun,Shen, Xiaoxia,Zhang, Dushan,Wang, Chunxiu,Wang, Tie-Lin,Briner, Karin,Bock, Mark G.
, p. 266 - 275 (2015)
Ergolines were recently identified as a novel class of H3 receptor (H3R) inverse agonists. Although their optimization led to drug candidates with encouraging properties for the treatment of narcolepsy, brain penetration remained low. To overcome this issue, ergoline 1 ((6aR,9R,10aR)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide)) was transformed into a series of indole derivatives with high H3R affinity. These new molecules were profiled by simultaneous determination of their brain receptor occupancy (RO) levels and pharmacodynamic (PD) effects in mice. These efforts culminated in the discovery of 15m ((R)-1-isopropyl-5-(1-(2-(2-methylpyrrolidin-1-yl)ethyl)-1H-indol-4-yl)pyridin-2(1H)-one), which has an ideal profile showing a strong correlation of PD effects with RO, and no measurable safety liabilities. Its desirably short duration of action was confirmed by electroencephalography (EEG) measurements in rats.
Phenylpyridine compound and preparation and application thereof
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Paragraph 0074-0076, (2021/03/13)
The invention discloses a phenylpyridine compound and preparation and application thereof. The compound is used as a tumor multidrug resistance reversal agent and a chemotherapeutic drug sensitizer. Pharmacological experiment results show that the compound provided by the invention has excellent tumor multidrug resistance reversal activity and sensitization chemotherapy drug activity, and can be clinically used as a malignant tumor multidrug resistance reversal agent and a chemotherapy drug sensitizer.
Synthesis of N-trifluoromethyl amides from carboxylic acids
Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
supporting information, p. 2245 - 2255 (2021/08/12)
Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.