- Structure-Based design of Marine-derived Meridianin C derivatives as glycogen synthase kinase 3β inhibitors with improved oral bioavailability: From aminopyrimidyl-indoles to the sulfonyl analogues
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Glycogen synthase kinase 3β (GSK-3β) has become an attractive target for the treatment of diabetes. Compound I is an indole-based GSK-3β inhibitor designed from the Meridianin C, a marine natural product (MNP) isolated from Aplidium meridianum. However, this compound has a moderate inhibitory activity toward GSK-3β (IC50 = 24.4 μM), moderate glucose uptake (38%), and especially, a low oral bioavailability (F = 11.4%). In the present study, applying the structure-based design strategy, a series of derivatives modified on the indole moiety were synthesized based on the lead compound I, followed by evaluating their cytotoxic activity, antihyperglycemic activity, and kinase inhibitory activity. Among this series, compound 6x with a sulfonyl group displayed the highest glucose uptake (83.5%) in muscle L6 cells, showing much higher inhibitory activity against GSK-3β (IC50 = 5.25 μM). Molecular docking indicated that compound 6x was properly inserted into the ATP-binding binding pocket of GSK-3β with a higher docking score (-8.145 kcal/mol) compared with that of compound I (-6.950 kcal/mol), interpreting the higher kinase inhibitory activity toward GSK-3β. Remarkably, compound 6x showed favorable drug-like properties, including significantly better oral bioavailability (F = 47.4%) and no two-week acute toxicity at a dose of 1 g/kg. Our findings suggest that these MNP-derived sulfonyl indole derivatives could be used as lead compounds for the development of anti-hyperglycemic drugs.
- Han, Shuwen,Zhou, Wei,Zhuang, Chunlin,Chen, Fener
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- Refinement of covalent EGFR inhibitor AZD9291 to eliminate off-target activity
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Non-small-cell lung cancer (NSCLC) is a major disease that accounts for 85% of all lung cancer cases which claimed around 1.8 billion lives worldwide in 2020. Tyrosine kinase inhibitors (TKIs) that target EGFR have been used for the treatment of NSCLC, but often develop drug resistance, and the covalent inhibitor AZD9291 has been developed to tackle the problem of drug resistance mediated by the T790M EGFR mutation; however, there is a side effect of hyperglycemia that may be due to off-target activity. This study examines analogs of AZD9291 by chemical proteomics, identifying analogs that maintain T790M-EGFR engagement while showing reduced cross-reactivity with off-targets.
- Bouffard, Elise,Cravatt, Benjamin,Dix, Melissa M.,Wong, Chi-Huey,Zaro, Balyn W.
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supporting information
(2021/05/29)
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- Structural modifications on indole and pyrimidine rings of osimertinib lead to high selectivity towards L858R/T790M double mutant enzyme and potent antitumor activity
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EGFR inhibitors represent a significant milestone for treatment of non-small cell lung cancer, however, they suffer from the acquired drug resistance. Utilizing osimertinib as the lead compound, this work has explored the structural modifications on the indole and pyrimidine rings of osimertinib to generate novel osimertinib derivatives. The in vitro enzymatic and cellular studies showed that the derivatives possessed high selectivity towards double mutant EGFR and potent antitumor activity. Particularly, compound 6b-1, the most active compound, exhibited excellent inhibitory activity against double mutant EGFR (IC50 = 0.18 nM) and wild-type EGFR (IC50 = 2.89 nM) as well as H1975 cells (IC50 = 1.44 nM). Western blot analysis showed that 6b-1 completely inhibited double mutant EGFR and Erk phosphorylation. In vivo test using xenograft model indicated that compound 6b-1 had better antitumor efficacy than osimertinib. More importantly, 6b-1 displayed many advantages in the pharmacokinetic study, including better oral bioavailability and metabolism character.
- Liu, Qiao,Luo, Yanli,Li, Zerui,Chen, Chen,Fang, Lei
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- Alkynyl-containing AZD9291 derivative, preparation method and application thereof
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The invention relates to an alkynyl-containing AZD9291 derivative, a preparation method and application thereof. The structural general formula (I) of the alkynyl-containing AZD9291 derivative is shown as the specification. Compared with the prior art, an AZD9291 analogue is synthesized and alkynyl is introduced, so that not only is the property of the AZD9291 analogue retained, but also the property of alkynyl is improved, the in-vitro antitumor activity is enhanced, and a good inhibition effect is achieved on a variety of tumor cells, and the alkynyl-containing AZD9291 derivative is an idealmedicine for treating diseases caused by EGFR mutation.
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Paragraph 0030-0033;0061
(2021/03/13)
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- Preparation method of 4-(1-cyclopropyl-1H-indole-3-yl)-N-phenylpyrimidine-2-amine derivative
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The invention relates to a preparation method of a 4-(1-cyclopropyl-1H-indole-3-yl)-N-phenylpyrimidine-2-amine derivative. The structural formula of the derivative is shown in the descriptions of theinvention. Specifically, the invention relates to a preparation method of a 4-(1-cyclopropyl-1H-indole-3-yl)-N-phenylpyrimidine-2-amine derivative with a compound structure as shown in a general formula (IV). According to the method, defects in the prior art are overcome, cost is greatly reduced, an obtained product is good in purity, high in yield and strong in process operability, and process safety is also greatly improved. Therefore, the preparation method and the application thereof are suitable for industrial application.
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Paragraph 0126-0133
(2020/09/12)
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- Deuterated pyrimidine derivative and application thereof
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The invention discloses a deuterated pyrimidine derivative and application thereof, and belongs to the field of medicines. The deuterated pyrimidine derivative and a pharmaceutically acceptable salt thereof have good activity of selectively inhibiting an
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Paragraph 0079-0082
(2020/07/15)
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- 2 - (2,Anilino) pyrimidine compound and application thereof (by machine translation)
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The invention relates to certain 2 - (2,anilino) pyrimidine compounds represented by the following formula I and application thereof. These compounds or salts thereof show a higher inhibition of EGFR than wild-type EGFR in the form of an activated or drug resistant mutant. Since the toxicity associated with the wild-type EGFR inhibition is reduced, it is expected that such a compound or salt thereof has excellent pharmacodynamic properties, higher metabolic stability, better blood-brain barrier permeability, and more suitable for use as a therapeutic agent, particularly for the treatment of cancer. , These compounds or salts thereof can be used to prepare EGFR-mediated diseases, in particular non-small cell lung cancer, for the treatment of certain mutated forms. (by machine translation)
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Paragraph 0105-0108
(2020/07/13)
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- Compound, containing conjugated dienamide structure, preparation method, pharmaceutical composition and application thereof
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The invention relates to a compound containing a conjugated allene amide structure and a preparation method, a medicine composition and application thereof, in particular to a compound containing a conjugated allene amide structure shown in a formula (I), and a preparation method, a medicine composition and application thereof in preparation of an EGFR (epidermal growth factor receptor) inhibitoror a medicine for preventing and/or treating EGFR-related diseases, especially cancers. (The formula (I) is shown in the description.).
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Paragraph 0180; 0181; 0182; 0183
(2020/03/19)
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- Preparation method for antagonizing drug-resistance anti-tumor EGFR (Epidermal Growth Factor Receptor) inhibitor
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The invention relates to a preparation method for an antagonizing drug-resistance anti-tumor EGFR (Epidermal Growth Factor Receptor) inhibitor. Specifically, the invention relates to a preparation method for a 4-(1-cyclopropyl-1H-indole-3-yl)-N-phenylpyrimidine-2-amine derivative of a compound structure shown in a general formula (IV). According to the method, defects in the prior art are overcome; cost is greatly shortened; an obtained product has high purity, high yield and high technical maneuverability; and technical safety is greatly improved. Therefore, the preparation method disclosed by the invention and the application of the preparation method are suitable for industrial application.
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Paragraph 0118; 0121-0125
(2019/06/07)
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- 2-(2, 4, 5-substituted aniline) pyrimidine derivative
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The invention relates to a 2-(2, 4, 5-substituted aniline) pyrimidine derivative, and more specifically discloses a compound represented by formula I or a pharmaceutically acceptable salt thereof, anda preparation method and applications of the compound represented by formula I and the pharmaceutically acceptable salt of the compound, wherein R1 to R9 are used for representing groups defined in the invention.
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Paragraph 0389-0392
(2019/11/21)
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- FLUORINE- AND/OR DEUTERIUM-CONTAINING COMPOUNDS FOR TREATING NON-SMALL CELL LUNG CANCER AND RELATED DISEASES
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Novel fluoride and/or deuterium-containing chemical, compounds useful for treating cancer or a related disease or disorder thereof, and pharmaceutical compositions and methods of preparation and use thereof.
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Paragraph 0102; 0104
(2019/06/14)
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- EGFR INHIBITORS
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Provided herein are compounds, salts, solid forms, and pharmaceutical compositions that are related to EGFR inhibitors, such as N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, as well as methods of preparing the same. Also provided herein are methods of using the compounds, salts, solid forms, and pharmaceutical compositions for the treatment of diseases or disorders, such as cancer.
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Page/Page column 36
(2020/01/10)
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- [(Indole -3 - yl) pyrimidine -2 - yl] amino haloalkylpropanamide -2 - enamide derivatives and salts, preparation method, application
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The invention provides a [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, a preparation method of the derivative, and application of the derivative and the salt. The [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative has a structure shown in the formula I below. Deuterium-carbon bonds in the derivative enable the derivative to decompose slowly in a human body, a medicament of the derivative has a longer half-life period and a higher concentration in blood, the dosage of the medicament is finally reduced, and toxic and side effects of the medicament are decreased. Experiments show that compared with AZD 9291 mesylates, AZD 929-D9 mesylate of the deuterium-substituted derivative has Cmax which is 1.32 times as high as that of AZD 9291, exposed dose 1.41 times as high as that of AZD 9291, and elimination half-life 1.31 times as long as that of AZD 9291.
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Paragraph 0034; 0117; 0118; 0119; 0120
(2018/08/03)
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- Phenylaminopyrimidine derivative used as ERK inhibitor
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The invention specifically relates to a novel phenylaminopyrimidine derivative used as an ERK inhibitor and a pharmaceutically acceptable salt thereof, belonging to the field of medical chemistry. Theinvention specifically discloses a compound as shown in a formula I which is described in the specification and a pharmaceutically acceptable salt and a pharmaceutical composition thereof, and a method for applying the compound to treatment of diseases resulting from ERK inhibition.
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Paragraph 0049; 0051; 0052
(2018/05/16)
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- 2,4-disubstituted benzene-1,5-diamine derivative used as EGFR (epidermal growth factor receptor) inhibitor and application of derivative
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The invention discloses a 2,4-disubstituted benzene-1,5-diamine derivative shown in a formula I as well as pharmaceutically acceptable salt, a stereoisomer, a solvate or a predrug of the derivative, with symbols defined in claims. The 2,4-disubstituted benzene-1,5-diamine derivative can inhibit activation or resistant mutation of one or more EGFRs (epidermal growth factor receptors), can be used for treating EGFR sensitive mutation cancer, can be applied to cases with secondary drug resistance in EGFR-TKI treatment at present and is an ideal treatment drug for diseases caused by EGFR mutation.
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Paragraph 0084; 0085; 0086
(2018/09/28)
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- EGFR INHIBITOR, AND PREPARATION AND APPLICATION THEREOF
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A 4-substituted-2-(N-(5-substituted allyl amide)phenyl)amino)pyrimidine derivative as represented by formula (I), and a preparation and application thereof as an EGFR inhibitor. The compound has activity of inhibiting the L858R EGFR mutant, the T790M EGFR mutant and the exon 19 deletion activating mutant, may be used to treat diseases mediated alone or in part by EGFR mutant activity, and has a wide application in drugs preventing and treating cancers, particularly non-small cell lung cancer.
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Paragraph 0106; 0512; 0513
(2017/09/02)
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- 2-(2,4,5-substituted aniline) pyrimidine derivative
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Disclosed is a 2-(2,4,5-substituted aniline) pyrimidine derivative. Disclosed are a compound shown in the formula (I) or pharmaceutically-acceptable salt thereof, a preparation method of the compound shown in the formula (I) or the pharmaceutically-acceptable salt thereof, a pharmaceutical composition containing the compound shown in the formula (I) or the pharmaceutically-acceptable salt thereof, and an application of the compound shown in the formula (I) or the pharmaceutically-acceptable salt thereof. In the formula (I), R1 to R6 are defined as shown in the application.
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Paragraph 0301-0304
(2017/09/01)
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- PYRIMIDINE OR PYRIDINE COMPOUNDS, PREPARATION METHOD THEREFOR AND PHARMACEUTICAL USES THEREOF
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The present invention disclosed a class of pyrimidine or pyridine compounds, pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof, preparation method therefor and pharmaceutical compositions and pharmaceutical uses thereof. The compounds can inhibit the variants of EGFR (Epidermis Growth Factor Receptor) proteinases, and therefore can inhibit the growth of a variety of tumor cells effectively. The compounds can be used to prepare antitumor drugs, used for the treatment, combined therapy or prevention of various different cancers. The compounds can overcome the drug resistance induced by the existing first-generation EGFR inhibitors such as gefitinib, erlotinib and so on. Particularly, the compounds can be used to prepare drugs for treating or preventing diseases, disturbances, disorders or conditions mediated by epidermis growth factor receptor variants (such as L858R activated mutants, Exon19 deletion activated mutants and T790M resistant mutants).
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Paragraph 0328-0330
(2017/09/19)
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- Pyrimidine compound as well as preparation method and medical application of pyrimidine compound
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The invention discloses a pyrimidine compound, a pharmaceutically-acceptable salt, a stereoisomer, a prodrug and a solvate thereof, as well as a preparation method, a pharmaceutical composition and medical application of the pyrimidine compound. This type of compound can generate an inhibitory effect on variant forms of EGFR (epidermal growth factor receptor) protease, so that the compound can effectively inhibit the growth of various tumor cells, can be used for preparing antitumor drugs, can be applied to treatment, combined treatment or prevention of many different cancers, and can overcome drug tolerance induced by first-generation EGFR inhibitors including existing drugs of gefitinib, erlotinib and the like. More particularly, this type of compound can be used for preparing medicines for treating or preventing diseases, obstacles, disorders or illness states mediated by certain epidermal growth-factor receptors with variant forms (for example, L858R active mutants, Exon19 deletion active mutants, and T790M resistant mutants).
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Paragraph 0078; 0079; 0080; 0081
(2017/08/28)
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- Substituted indole or indole pyrimidine derivative as well as preparation method and application of substituted indole or indole pyrimidine derivative
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The invention relates to a substituted indole or an indole pyrimidine derivative as well as a preparation method, a pharmaceutical composition and application of the substituted indole or the indole pyrimidine derivative, in particular relates to a compou
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Paragraph 0125; 0127-0129
(2017/09/01)
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- DEUTERATED COMPOUNDS FOR TREATING CANCER AND RELATED DISEASES AND CONDITIONS, AND COMPOSITIONS AND METHODS THEREOF
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The invention provides novel chemical compounds useful for treating cancer or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.
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Paragraph 00101
(2017/07/31)
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- Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor
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Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
- Finlay, M. Raymond V.,Anderton, Mark,Ashton, Susan,Ballard, Peter,Bethel, Paul A.,Box, Matthew R.,Bradbury, Robert H.,Brown, Simon J.,Butterworth, Sam,Campbell, Andrew,Chorley, Christopher,Colclough, Nicola,Cross, Darren A. E.,Currie, Gordon S.,Grist, Matthew,Hassall, Lorraine,Hill, George B.,James, Daniel,James, Michael,Kemmitt, Paul,Klinowska, Teresa,Lamont, Gillian,Lamont, Scott G.,Martin, Nathaniel,McFarland, Heather L.,Mellor, Martine J.,Orme, Jonathon P.,Perkins, David,Perkins, Paula,Richmond, Graham,Smith, Peter,Ward, Richard A.,Waring, Michael J.,Whittaker, David,Wells, Stuart,Wrigley, Gail L.
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p. 8249 - 8267
(2014/12/11)
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- Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR)
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A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
- Ward, Richard A.,Anderton, Mark J.,Ashton, Susan,Bethel, Paul A.,Box, Matthew,Butterworth, Sam,Colclough, Nicola,Chorley, Christopher G.,Chuaqui, Claudio,Cross, Darren A.E.,Dakin, Les A.,Debreczeni, Judit é.,Eberlein, Cath,Finlay, M. Raymond V.,Hill, George B.,Grist, Matthew,Klinowska, Teresa C.M.,Lane, Clare,Martin, Scott,Orme, Jonathon P.,Smith, Peter,Wang, Fengjiang,Waring, Michael J.
-
supporting information
p. 7025 - 7048
(2013/10/01)
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- 2 - (2, 4, 5 - SUBSTITUTED -ANILINO) PYRIMIDINE DERIVATIVES AS EGFR MODULATORS USEFUL FOR TREATING CANCER
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The present invention relates to certain 2-(2,4,5-substituted-anilino) pyrimidine compounds and pharmaceutically acceptable salts thereof which may be useful in the treatment or prevention of a disease or medical condition mediated through certain mutated forms of epidermal growth factor receptor (for example the L858R activating mutant, the Exonl9 deletion activating mutant and the T790M resistance mutant). Such compounds and salts thereof may be useful in the treatment or prevention of a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, especially useful polymorphic forms of these compounds and salts, intermediates useful in the manufacture of said compounds and to methods of treatment of diseases mediated by various different forms of EGFR using said compounds and salts thereof.
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Page/Page column 139
(2013/03/26)
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- One-pot synthesis of meridianins and meridianin analogues via indolization of nitrosoarenes
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Meridianins, marine alkaloids known as kinase inhibitors with an indole skeleton, and meridianin analogues were produced regioselectively and in moderate to good yields by thermal annulation of nitrosoarenes with 2-amino-4-ethynylpyrimidine and 2-chloro-4-ethynylpyrimidine, respectively, through a novel and atom-economical indolization process.
- Tibiletti, Francesco,Simonetti, Marco,Nicholas, Kenneth M.,Palmisano, Giovanni,Parravicini, Matteo,Imbesi, Federico,Tollari, Stefano,Penoni, Andrea
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experimental part
p. 1280 - 1288
(2010/04/02)
-
- JNK modulators
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Compounds of formula I modulate JNK: wherein the variables are as defined herein.
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-
- Synthesis and SAR of aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors
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The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed.
- Alam, Mahbub,Beevers, Rebekah E.,Ceska, Tom,Davenport, Richard J.,Dickson, Karen M.,Fortunato, Mara,Gowers, Lewis,Haughan, Alan F.,James, Lynwen A.,Jones, Mark W.,Kinsella, Natasha,Lowe, Christopher,Meissner, Johannes W.G.,Nicolas, Anne-Lise,Perry, Benjamin G.,Phillips, David J.,Pitt, William R.,Platt, Adam,Ratcliffe, Andrew J.,Sharpe, Andrew,Tait, Laura J.
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p. 3463 - 3467
(2008/02/09)
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