4385-77-7Relevant articles and documents
Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors
Engelhardt, Harald,B?se, Dietrich,Petronczki, Mark,Scharn, Dirk,Bader, Gerd,Baum, Anke,Bergner, Andreas,Chong, Eugene,D?bel, Sandra,Egger, Georg,Engelhardt, Christian,Ettmayer, Peter,Fuchs, Julian E.,Gerstberger, Thomas,Gonnella, Nina,Grimm, Andreas,Grondal, Elisabeth,Haddad, Nizar,Hopfgartner, Barbara,Kousek, Roland,Krawiec, Mariusz,Kriz, Monika,Lamarre, Lyne,Leung, Joyce,Mayer, Moriz,Patel, Nitinchandra D.,Simov, Biljana Peric,Reeves, Jonathan T.,Schnitzer, Renate,Schrenk, Andreas,Sharps, Bernadette,Solca, Flavio,Stadtmüller, Heinz,Tan, Zhulin,Wunberg, Tobias,Zoephel, Andreas,McConnell, Darryl B.
, p. 10272 - 10293 (2019)
The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.
N-(1H-IMIDAZOL-2-YL)BENZAMIDE COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AS ACTIVE INGREDIENT
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, (2021/04/10)
N-(1H-imidazol-2-yl)benzamide compound of formula (I), or a pharmaceutically acceptable salt, a prodrug, a solvate, or a stereoisomer thereof which is a novel compound exhibiting excellent inhibitory activity against IRAK-4, can be used without side effects for efficient prevention and treatment of diseases mediated by IRAK-4 receptors, particularly autoimmune diseases or lymphomas.
Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain
Bi, Xiaoyang,Chen, Kaixian,Chen, Yu,Ding, Hong,Jiang, Hao,Jiang, Hualiang,Lu, Tian,Lu, Wenchao,Luo, Cheng,Sun, Zhongya,Xu, Pan,Zhang, Fengcai,Zhang, Naixia,Zhou, Bing
supporting information, (2020/06/21)
CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacetylation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 ± 0.3 μM. We obtained a high-resolution co-crystal structure of the CBP bromodomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 ± 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bromodomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.
New Pyrazolecarboxylic compd., its manufacturing method and pest control agents
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Paragraph 0142; 0143; 0144, (2018/05/03)
PROBLEM TO BE SOLVED: To provide a new pyrazole compound capable of showing excellent biological activity to not only spider mites but also Nematoda. SOLUTION: It is found that a new pyrazole compound having a nitrogen-containing hetero ring in a first position of a pyrazole ring and a sulfonate group in a fifth position shows excellent biological activity to not only the spider mites but also the Nematoda. COPYRIGHT: (C)2012,JPOandINPIT
Quantification of the effect of conformational restriction on supramolecular effective molarities
Adams, Harry,Chekmeneva, Elena,Hunter, Christopher A.,Misuraca, Maria Cristina,Navarro, Cristina,Turega, Simon M.
, p. 1853 - 1863 (2013/04/10)
The association constants for a family of 96 closely related zinc porphyrin-pyridine ligand complexes have been measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). The zinc porphyrin receptors are equipped with phenol side arms, which can form intramolecular H-bonds with ester or amide side arms on the pyridine ligands. These association constants were used to construct 64 chemical double mutant cycles, which measure the free energy contributions of intramolecular H-bonding interactions to the overall stability of the complexes. Measurement of association constants for the corresponding intermolecular H-bonding interactions allowed determination of the effective molarities (EM) for the intramolecular interactions. Comparison of ligands that feature amide H-bond acceptors and ester H-bonds at identical sites on the ligand framework show that the values of EM are practically identical. Similarly, the values of EM are practically identical in toluene and in TCE. However, comparison of two ligand series that differ by one degree of torsional freedom shows that the values of EM for the flexible ligands are an order of magnitude lower than for the corresponding rigid ligands. This observation holds for a range of different supramolecular architectures with different degrees of receptor-ligand complementarity and suggests that in general the cost of freezing a rotor in supramolecular complexes is of the order of 5 kJ/mol.
BENZOXAZOLE CARBOXAMIDE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)
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Page/Page column 76, (2009/08/16)
A compound having the structure set forth in Formula (I) or Formula (II): wherein the variables Y, R1, R2, R3, and R4 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.
A convenient synthesis of heteroaryl benzoic acids via Suzuki reaction
Gong, Yong,Pauls, Henry W.
, p. 829 - 831 (2007/10/03)
An one step approach to heteroaryl benzoic acids from readily accessible heteroaryl halides and carboxybenzene boronic acids is described. The Suzuki coupling is carried out in the presence of Pd(PPh3)4 and sodium carbonate in aqueous acetonitrile. The scope and limitations of the reaction are discussed.
3-Phenylpiperidines. Central Dopamine-Autoreceptor Stimulating Activity
Hacksell, Uli,Arvidsson, Lars-Erik,Svensson, Uno,Nilsson, J. Lars G.
, p. 1475 - 1482 (2007/10/02)
Thirty compounds related to the selective dopamine-autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine have been synthesized and tested for central dopamine-autoreceptor stimulating activity.The 3-(3-hydroxyphenyl)piperidine moiety seems indispensable for high potency and selectivity.Introduction of an additional hydroxyl group into the 4-position of the aromatic ring gives a compound with dopaminergic activity but lacking selectivity for autoreceptors. 3-(3-Hydroxyphenyl)-N-n-propylpyrrolidine, 3-(3-hydroxy)-N-n-propylperhydroazepine, and 3-(3-hydroxyphenyl)quinuclidine were all inactive.The most potent compounds were the N-isopropyl-, N-n-butyl-, N-n-pentyl-, and N-phenethyl-substituted 3-(3-hydroxyphenyl)piperidine derivatives.None of the compounds investigated seemed to have central noradrenaline- or serotonin-receptor stimulating activity.
