- Synthesis and apoptotic activity of new pyrazole derivatives in cancer cell lines
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We designed and synthesized new pyrazole thiourea chimeric derivatives and confirmed their structures by NMR and IR spectra. Apoptotic effects were studied in human cancer cells. The N-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-N′-(3-bromophenyl)-thiourea compo
- Nitulescu, George Mihai,Draghici, Constantin,Olaru, Octavian Tudorel,Matei, Lilia,Ioana, Aldea,Dragu, Laura Denisa,Bleotu, Coralia
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- Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors
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Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC50 = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC50 = 0.36 ± 0.11 μM, as well as less toxicity against normal GES-1 cells with IC50 = 187.46 ± 10.13 μM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.
- Wang, Xing-Rong,Wang, Shuai,Li, Wen-Bo,Xu, Kai-Yan,Qiao, Xue-Peng,Jing, Xue-Li,Wang, Zi-Xiao,Yang, Chang-jiang,Chen, Shi-Wu
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supporting information
(2021/01/26)
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- POLYMORPHS OF (R)-N-(5-(5-ETHYL-1,2,4-OXADIAZOL-3-YL)-2,3-DIHYDRO-1H-INDEN-1-YL)-1-METHYL-1H-PYRAZOLE-4-CARBOXAMIDE
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Provided herein are polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, compositions thereof, methods of preparation thereof, and methods of their uses.
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Paragraph 0161-0162
(2021/02/12)
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- Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy
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Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery of an Indane analogue (12) with a less restrictive structure-activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life (t1/2) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.
- Ashcraft, Luke,Chin, Eva R.,Chuang, Chihyuan,Collibee, Scott,Cremin, Peadar,Hartman, James,Hwee, Darren T.,Malik, Fady I.,Morgan, Bradley P.,Robertson, Laura A.,Schaletzky, Julia,Vander Wal, Mark,Wang, Jingying,Wang, Wenyue,Wang, Xiaolin,Wehri, Eddie,Wu, Yangsong,Zamora, Jeanelle
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supporting information
p. 14142 - 14152
(2021/10/20)
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- NOVEL NUCLEOSIDE OR NUCLEOTIDE DERIVATIVES, AND USES THEREOF
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The present disclosure relates to a novel nucleoside or nucleotide derivative, a racemate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating viral infection-associated diseases, containing the same as an active ingredient.
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Paragraph 0064
(2020/12/10)
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- Synthesis and antifungal activity of carvacrol and thymol esters with heteroaromatic carboxylic acids
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Aiming to obtain the more effective pathogen inhibitive ingredients and explore the influence of introducing different heterocyclic units to carvacrol and thymol esters, twenty ester derivatives with different heterocyclic units were synthesized. And the
- Fan, Liming,Jiang, Shanshan,Su, Fawu,Wang, Kaibo,Yang, Yunhai,Ye, Min
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p. 1924 - 1930
(2018/06/11)
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- NAPHTHYRIDINES AS INHIBITORS OF HPK1
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Naphthyridine compounds and their use as inhibitors of HPK1 are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the naphthyridine compounds.
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Paragraph 1066; 1067
(2018/10/21)
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- INDAZOLYL THIADIAZOLAMINES AND RELATED COMPOUNDS FOR INHIBITION OF RHO-ASSOCIATED PROTEIN KINASE AND THE TREATMENT OF DISEASE
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The invention provides indazolyl thiadiazolamines and related compounds, pharmaceutical compositions, methods of inhibiting Rho-associated protein kinase, and methods of treating inflammatory disorders, immune disorders, fibrotic disorders, and other medical disorders using such compounds. An exemplary indazolyl thiadiazolamine compound is an N-(5-[5-[(1H4ndazol-5-yl)amino]-1,3,4-thiadiazol-2-yl]pyridin-3-yl)acetamide compound.
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Paragraph 00400
(2016/09/22)
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- Pyrazole ketone compound or its salt, preparation method thereof, and use of the herbicide composition (by machine translation)
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This application pertains to the field of agricultural chemicals, in particular to a pyrazole ketone compound or its salt, preparation method, herbicidal composition and use. The ketone compounds states the pyrazole shown as formula I: In the formula, R 1 R 2 N representative containing substituted or unsubstituted 1-3 of the aza-3-8-membered nitrogen-containing heterocyclic base; or R 1, R 2 respectively represents hydrogen, C 1-8 alkyl etc.; R 3 representative hydrogen, C 1-4 alkyl, alkenyl, alkynyl, or unsubstituted C 1-4 alkyl substituted C 3-6 cycloalkyl; R 4 represents methyl, ethyl, n-propyl, isopropyl, cyclopropyl; X represents hydrogen, -S (O) n R 6, -R 7, containing substituted or unsubstituted 1-4 of the aza-3-8-membered heterocyclic group, wherein n representative 1, 2, 3, R 6 represents a substituted or unsubstituted alkyl or aryl, R 7 represents a substituted or unsubstituted alkyl, aryl, alkanoyl or sweet-smelling acyl. The present invention provides good efficacy of the pharmaceutical actives, easy to use, low cost, has good commercial value. (by machine translation)
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Paragraph 0133; 0134; 0135
(2016/10/08)
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- Nickel(II)-Mediated Regioselective C H Monoiodination of Arenes and Heteroarenes by using Molecular Iodine
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The 8-aminoquinoline-directed, nickel(II)-mediated ortho-iodination of benzamides using molecular iodine has been developed. The process is highly regioselective and furnishes only monoiodinated products. A broad range of arenes and heteroarenes with diverse functional groups provided monoiodinated products in good to excellent yields. (Figure presented.) .
- Khan, Bhuttu,Kant, Ruchir,Koley, Dipankar
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supporting information
p. 2352 - 2358
(2016/07/28)
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- Directing Group-Assisted Copper(II)-Catalyzed ortho-Carbonylation to Benzamide using 2,2′-Azobisisobutyronitrile (AIBN)
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An efficient copper-catalyzed regioselective C—H bond carbonylation of benzamides has been developed using 2,2′-azobisisobutyronitrile (AIBN) as traceless cyanating agent. The non-toxic and readily available AIBN was used for the carbonylative cyclization
- Khan, Bhuttu,Khan, Afsar Ali,Kant, Ruchir,Koley, Dipankar
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supporting information
p. 3753 - 3758
(2016/12/16)
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- Dual role of Rh(III) catalyst enables regioselective halogenation of (electron-rich) heterocycles
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The Rh(III)-catalyzed selective bromination and iodination of electron-rich heterocycles is reported. Kinetic investigations show that Rh plays a dual role in the bromination, catalyzing the directed halogenation and preventing the inherent halogenation of these substrates. As a result, this method gives highly selective access to valuable halogenated heterocycles with regiochemistry complementary to those obtained using uncatalyzed approaches, which rely on the inherent reactivity of these classes of substrates. Furans, thiophenes, benzothiophenes, pyrazoles, quinolones, and chromones can be applied.
- Schr?der, Nils,Lied, Fabian,Glorius, Frank
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supporting information
p. 1448 - 1451
(2015/02/19)
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- PRODRUG BIPYRIDYLAMINOPYRIDINES AS SYK INHIBITORS
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The present invention provides compounds of Formula (I), which are prodrugs of trans-4-[(1R)-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid, a potent inhibitor of Syk. The compounds are useful in the treatment and prevention of diseases mediated by the enzyme, such as asthma, COPD, rheumatoid arthritis and cancer.
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Page/Page column 73
(2014/05/24)
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- NITROGEN-CONTAINING FUSED RING COMPOUNDS FOR USE AS CRTH2 ANTAGONISTS
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The present application relates to nitrogen-containing fused ring compounds shown by general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof as CRTH2 antagonist, wherein X1, X2, X3, X4, X5, W, X, Y, L1, L2, L3, A, B are as defined in the description; the present application further relates to a method for preparing the compounds, a pharmaceutical formulation and a pharmaceutical composition comprising the compounds, a use of the compounds for the manufacture of a medicament for the treatment and/or prevention of diseases related to activity of CRTH2.
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Paragraph 0149
(2014/11/13)
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- NITROGEN-CONTAINING FUSED RING COMPOUNDS AS CRTH2 ANTAGONISTS
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The present application relates to nitrogen-containing fused ring compounds shown by general formula (I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof as CRTH2 antagonist, wherein X1, X2, X3, X4, X5, W, X, Y, L1, L2, L3, A, B are as defined in the description; the present application further relates to a method for preparing the compounds, a pharmaceutical formulation and a pharmaceutical composition comprising the compounds, a use of the compounds for the manufacture of a medicament for the treatment and/or prevention of diseases related to activity of CRTH2.
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Paragraph 0292
(2014/10/16)
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- PYRIDINONE AND PYRIMIDINONE DERIVATIVES AS FACTOR XIA INHIBITORS
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The present invention provides compounds of the general formula (I), their salts and N- oxides, and solvates and prodrugs thereof (wherein the characters are as defined in the description). The compounds of the general formula (I) are inhibitors of Factor XIa, so that they are useful in the prevention of and/or therapy for thromboembolic diseases.
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Page/Page column 230; 231
(2013/07/05)
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- NOVEL DIHYDROPYRIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS AND NEUROKININ-3 RECEPTOR ANTAGONISTS
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The present invention is directed to novel dihydropyridin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors and/or Neurokinin-3 (NK3) receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 48
(2012/02/02)
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- Synthesis and antimicrobial screening of N-(1-methyl-1H-pyrazole-4- carbonyl)-thiourea derivatives
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In the search of bioactive molecules in the class of functionally 4-substituted pyrazolic compounds, a series of N-(1-methyl-1H-pyrazole-4- carbonyl)-thiourea derivatives were prepared by addition of various substituted anilines to 1-methyl-1H-pyrazole-4-
- Nitulescu, George M.,Draghici, Constantin,Chifiriuc, Mariana C.,Marutescu, Luminita,Bleotu, Coralia,Missir, Alexandru V.
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experimental part
p. 308 - 314
(2012/08/28)
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- The discovery of MK-4256, a potent SSTR3 antagonist as a potential treatment of type 2 diabetes
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A structure-activity relationship study of the imidazolyl-β- tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.
- He, Shuwen,Ye, Zhixiong,Truong, Quang,Shah, Shrenik,Du, Wu,Guo, Liangqin,Dobbelaar, Peter H.,Lai, Zhong,Liu, Jian,Jian, Tianying,Qi, Hongbo,Bakshi, Raman K.,Hong, Qingmei,Dellureficio, James,Pasternak, Alexander,Feng, Zhe,Dejesus, Reynalda,Yang, Lihu,Reibarkh, Mikhail,Bradley, Scott A.,Holmes, Mark A.,Ball, Richard G.,Ruck, Rebecca T.,Huffman, Mark A.,Wong, Frederick,Samuel, Koppara,Reddy, Vijay B.,Mitelman, Stan,Tong, Sharon X.,Chicchi, Gary G.,Tsao, Kwei-Lan,Trusca, Dorina,Wu, Margaret,Shao, Qing,Trujillo, Maria E.,Eiermann, George J.,Li, Cai,Zhang, Bei B.,Howard, Andrew D.,Zhou, Yun-Ping,Nargund, Ravi P.,Hagmann, William K.
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supporting information; experimental part
p. 484 - 489
(2012/10/08)
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- An efficient synthesis of isomeric 1-(1-Alkyl-1H-pyrazolyl) ethanones
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A simple and versatile general method for the preparation of N-substituted 3-, 4-, or 5-acetylpyrazoles from corresponding acids via hydrolysis and decarboxylation of substituted diethyl [(1-alkyl-1H-pyrazolyl)carbonyl]malonates was developed. Title compounds were prepared in three steps without isolation of intermediates in 48-82% overall yield.
- Taydakov, Ilya,Krasnoselskiy, Sergey
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p. 1422 - 1424
(2013/02/23)
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- NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 153
(2011/04/24)
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- Synthesis of new pyrazole derivatives and their anticancer evaluation
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A series of functionally substituted pyrazole compounds have been synthesized and evaluated in vitro for their antiproliferative effects on a panel of 60 cellular lines, according to the National Cancer Institute screening protocol. Three of the 12 tested compounds showed moderate antitumor activity, one of them being chosen for the 5-dose assay and presented logGI50 values up to -5.75.
- Nitulescu, George Mihai,Draghici, Constantin,Missir, Alexandru Vasile
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experimental part
p. 4914 - 4919
(2010/12/20)
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- Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
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We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
- Shi, Yan,Li, Chi,O'Connor, Stephen P.,Zhang, Jing,Shi, Mengxiao,Bisaha, Sharon N.,Wang, Ying,Sitkoff, Doree,Pudzianowski, Andrew T.,Huang, Christine,Klei, Herbert E.,Kish, Kevin,Yanchunas Jr., Joseph,Liu, Eddie C.-K.,Hartl, Karen S.,Seiler, Steve M.,Steinbacher, Thomas E.,Schumacher, William A.,Atwal, Karnail S.,Stein, Philip D.
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scheme or table
p. 6882 - 6889
(2010/07/03)
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- Pyrazole analogues of prazosin
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A series of analogues of prazosin, in which 1-methyl or 1- phenylpyrazole moieties were substituted for the furan ring, were synthesized and studied for their α1-adrenoceptor antagonist activity. The role of the five member heterocyclic substru
- Ermondi, Giuseppe,Boschi, Donatella,Di Stilo, Antonella,Tironi, Carla,Gasco, Alberto
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p. 519 - 524
(2007/10/03)
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