3:;
16130-58-8Relevant articles and documents
Identification and Optimization of Novel Cathepsin C Inhibitors Derived from EGFR Inhibitors
Hou, Weijie,Sun, Huan,Ma, Yongfen,Liu, Chunyan,Zhang, Zhiyuan
, p. 5901 - 5919 (2019)
In the course of developing the biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we herein unexpectedly discovered that the epidermal growth factor receptor irreversible inhibitor WZ4002 also functioned as a low micromolar inhibitor of cathepsin C (CatC), a promising target for the treatment of numerous inflammatory and autoimmune diseases. Building on from this discovery, and following structure-activity relationship investigations guided by computational modeling, a novel series of pyridine scaffold compounds were developed as irreversible CatC inhibitors, further culminated in identifying a highly potent and selective inhibitor 22, which displays good metabolic stability and oral bioavailability. In vivo studies revealed that compound 22 clearly displays the ability to inhibit CatC, consequently leading to efficient inhibition of downstream neutrophil serine proteases in both bone marrow and blood. The overall excellent profile of compound 22 made it an interesting candidate for further preclinical investigation.
Quantification of CH...π interactions: Implications on how substituent effects influence aromatic interactions
Gung, Benjamin W.,Emenike, Bright U.,Lewis, Michael,Kirschbaum, Kristin
, p. 12357 - 12362 (2010)
Attractive interactions between a substituted benzene ring and an α-substituted acetate group were determined experimentally by using the triptycene model system. The attractive interaction correlates well with the Hammett constants σm (R2=0.90), but correlates much better with the acidity of the α-protons (R2=0.98). A predominant CH...π interaction was found to control the conformational preference of model compounds 1a-g. Despite the predominance of the CH...π interaction in compounds 1a-g, a Hammett plot displays a fairly straight line for the substituent effect. These results show that when using Hammett plots in a simplified model system, a system designed to study the effect of X...π interactions could capture the X-H...π interaction instead.
Stable enols of amides ArNHC(OH)=C(CN)CO2R. E/Z enols, equilibria with the amides, solvent effects, and hydrogen bonding
Lei, Yi Xiong,Casarini, Daniele,Cerioni, Giovanni,Rappoport, Zvi
, p. 947 - 959 (2003)
The structures of anilido cyano(fluoroalkoxycarbonyl)methanes ArNHCOCH(CN)CO2R, where r = CH2CF3 or CH(CF3)2, Ar = p-XC6H4, and X = MeO, Me, H, or Br, were investigated. In the solid state, all exist as the enols ArNHC(OH)=C(CN)CO2R 7 (R = CH2CF3) and 9 (R = CH(CF3)2) with cis arrangement of the hydrogen-bonded ROC=O...HO moiety and a long C1=C2 bond. The product composition in solution is solvent dependent. In CDCl3 solution, only a single enol is observed, whereas in THF-d8 and CD3CN, two enols (E and Z) are the major products, and the amide is the minor product or not observed at all (KEnol 1.04-9 (CD3CN, 298 K) and 3 to ≥100 (THF, 300 K)). The percentage of the amide and the Z-enol increase upon an increase in temperature. In all solvents, the percent enol is higher for 9 than for 7. In CD3CN, more enol is observed when the aryl group is more electron-donating. The spectra in DMSO-d6 and DMF-d7 indicate the presence of mostly a single species, whose spectra do not change on addition of a base and is ascribed to the anion of the ionized carbon acid. Comparison with systems where the CN is replaced by a CO2R group (R = CH2CF3, CH(CF3)2) shows a higher percentage of enol for the CN-substituted system. Intramolecular (to CO2R) and intermolecular hydrogen bonds determine, to a significant extent, the stability of the enols, their Z/E ratios (e.g., Z/E (THF, 240 K) = 3.2-4.0 (7) and 0.9-1.3 (9)), and their δ(OH) in the 1H spectra. The interconversion of Z- and E-enol by rotation around the C=C bond was studied by DNMR, and ΔG? values of ≥15.3 and 14.1 ± 0.4 kcal/mol for Z-7 and Z-9 were determined. Features of the NMR spectra of the enols and their anions are discussed.
Cyanoketene: The microwave spectrum and structure of an unstable molecule
Hahn,Bodenseh,Ferner
, p. 138 - 147 (2004)
The unstable molecule cyanoketene has been prepared by pyrolysis in a flow system, and the microwave spectra of five isotopic species, a- and b-type, have been measured in the frequency range from 8 to 40 GHz. Precise rotational constants and centrifugal distortion parameters up to the sixth order were obtained. The molecule has been shown to be planar, and a reliable structure was derived, Also the N-quadrupole coupling constants and the dipole moment components have been determined. The results could be a basis for interstellar spectroscopy of this molecule.
CHEMICAL COMPOUNDS
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Paragraph 0414-0416, (2021/04/02)
The present disclosure describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, auto-immune diseases, cancer, and other disorders and indications where modulation of JAK would be desirable. Also described herein are methods of treating inflammation, auto-immune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound herein described.
KRAS MUTANT PROTEIN INHIBITOR
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Page/Page column 51-52; 55-56, (2021/05/15)
Provided herein are a KRAS mutant protein inhibitor, as shown by formula (I), a composition containing the inhibitor and the use thereof.
SUBSTITUTED BICYCLIC COMPOUNDS USEFUL AS T CELL ACTIVATORS
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Paragraph 0475; 0476, (2021/06/26)
Disclosed are compounds of Formula (I): or a salt thereof, wherein: X is CR6 or N; Y is CR3 or N; R1, R2, R3, R4, R5, R6, R7, and m are defined herein. Also disclosed are methods of using such compounds to inhibit the activity of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ), and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.
