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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.
KRAS MUTANT PROTEIN INHIBITORS
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Paragraph 0201; 0203, (2021/04/02)
The invention relates to a KRAS mutant protein inhibitor, a composition containing the inhibitor and the use thereof.
KRAS MUTANT PROTEIN INHIBITORS
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Page/Page column 38-39, (2021/06/26)
The invention relates to a KRAS mutant protein inhibitor shown as formula (I), a composition containing the inhibitor and the use thereof.
Fused pyrimidine derivative, and preparation method thereof and application of fused pyrimidine derivative in medicine
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Paragraph 0271-0276, (2021/07/21)
The invention relates to a fused pyrimidine derivative, and a preparation method thereof and application of the fused pyrimidine derivative in medicine. Specifically, the invention relates to a fused pyrimidine derivative shown in a general formula (I), a preparation method of the fused pyrimidine derivative, a pharmaceutical composition containing the derivative and application of the fused pyrimidine derivative as a therapeutic agent, especially application of the fused pyrimidine derivative as an ATR kinase inhibitor and application of the fused pyrimidine derivative in preparation of drugs for treating or preventing hyperproliferative diseases.
