- Solid-phase synthesis of benzimidazole libraries biased for RNA targets
-
An efficient and highly versatile synthesis of two libraries 1(x,y) and 2-Ar(x,y,z) or 2-R2(x,y,w) based on the privileged benzimidazole scaffold is described. Our design is aimed at obtaining molecules, biased for binding to RNA targets, by in
- Vourloumis, Dionisios,Takahashi, Masayuki,Simonsen, Klaus B.,Ayida, Benjamin K.,Barluenga, Sofia,Winters, Geoffrey C.,Hermann, Thomas
-
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Read Online
- Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γagonists/Soluble Epoxide Hydrolase Inhibitors
-
Polypharmaceutical regimens often impair treatment of patients with metabolic syndrome (MetS), a complex disease cluster, including obesity, hypertension, heart disease, and type II diabetes. Simultaneous targeting of soluble epoxide hydrolase (sEH) and p
- Lillich, Felix F.,Willems, Sabine,Ni, Xiaomin,Kilu, Whitney,Borkowsky, Carmen,Brodsky, Mirko,Kramer, Jan S.,Brunst, Steffen,Hernandez-Olmos, Victor,Heering, Jan,Schierle, Simone,Kestner, Roxane-I.,Mayser, Franziska M.,Helmst?dter, Moritz,G?bel, Tamara,Weizel, Lilia,Namgaladze, Dmitry,Kaiser, Astrid,Steinhilber, Dieter,Pfeilschifter, Waltraud,Kahnt, Astrid S.,Proschak, Anna,Chaikuad, Apirat,Knapp, Stefan,Merk, Daniel,Proschak, Ewgenij
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supporting information
p. 17259 - 17276
(2021/12/09)
-
- COMPOUNDS WITH ANTIMICROBIAL ACTIVITY
-
Provided herein are compounds useful in the treatment of bacterial infections, pharmaceuticals comprising the same, and methods of use and preparation thereof.
- -
-
Paragraph 0262-0264; 0397-0399
(2020/01/24)
-
- Preparation method of 3-acetylindole BRPF1 inhibitor and use of 3-acetylindole BRPF1 inhibitor
-
The invention relates to a 3-acetylindole compound of a novel structure shown in a formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or a solvate thereof, a preparation method of the compound, a pharmaceutical composition containing a therapeutically effective dose of the compound, and use thereof as a protein tyrosine kinase inhibitor, especially as a bromine-containing area PHD zinc finger protein 1 (BRPF1) inhibitor, in the prevention or treatment of disease benefited from the inhibition of BRPF1.
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Page/Page column 0094;0095; 0276-0278
(2020/03/03)
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- ACLY INHIBITORS AND USES THEREOF
-
The present invention provides compounds useful as inhibitors of ATP citrate lyase (ACLY), compositions thereof, and methods of using the same.
- -
-
Paragraph 00493
(2020/06/01)
-
- Synthesis, docking, 3-D-qsar, and biological assays of novel indole derivatives targeting serotonin transporter, dopamine D2 receptor, and mao-a enzyme: In the pursuit for potential multitarget directed ligands
-
A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a-o) and (2-{4-[3-(1H-3-indolyl) -propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a-l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).
- Alarcón-Espósito, Jazmín,Araya-Maturana, Ramiro,Cabezas, David,Cerda-Cavieres, Christopher,Chung, Hery,Iturriaga-Vásquez, Patricio,Mella-Raipán, Jaime,Ojeda-Gómez, Claudia,Pessoa-Mahana, Carlos D.,Pessoa-Mahana, Hernán,Quiroz, Gabriel,Reyes-Parada, Miguel,Rodríguez-Lavado, Julio,Saitz, Claudio
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-
- Discovery of Antibacterials That Inhibit Bacterial RNA Polymerase Interactions with Sigma Factors
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Formation of a bacterial RNA polymerase (RNAP) holoenzyme by a catalytic core RNAP and a sigma (σ) initiation factor is essential for bacterial viability. As the primary binding site for the housekeeping σ factors, the RNAP clamp helix domain represents an attractive target for novel antimicrobial agent discovery. Previously, we designed a pharmacophore model based on the essential amino acids of the clamp helix, such as R278, R281, and I291 (Escherichia coli numbering), and identified hit compounds with antimicrobial activity that interfered with the core-σ interactions. In this work, we rationally designed and synthesized a class of triaryl derivatives of one hit compound and succeeded in drastically improving the antimicrobial activity against Streptococcus pneumoniae, with the minimum inhibitory concentration reduced from 256 to 1 μg/mL. Additional characterization of antimicrobial activity, inhibition of transcription, in vitro pharmacological properties, and cytotoxicity of the optimized compounds demonstrated their potential for further development.
- Ye, Jiqing,Chu, Adrian Jun,Harper, Rachel,Chan, Shu Ting,Shek, Tsun Lam,Zhang, Yufeng,Ip, Margaret,Sambir, Mariya,Artsimovitch, Irina,Zuo, Zhong,Yang, Xiao,Ma, Cong
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p. 7695 - 7720
(2020/07/21)
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- Substituent effects on the isomerization of hydrazone switches driven by the intramolecular hydrogen bond
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In this work, the substituent effects on hydrogen bonding in one kind of hydrazone-based switch are revealed. The E/Z isomerization ratios of these hydrazones and their intramolecular hydrogen bond strengths in the Z form were evaluated using NMR technique. Linear correlations between these parameters and Hammett empirical values for substituent effects are explored as well.
- Lu, Chaocao,Htan, Bu,Fu, Shitao,Ma, Chunmiao,Gan, Quan
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p. 4010 - 4016
(2019/07/03)
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- Thiazole-containing propyne amide derivative as well as preparation method and pharmaceutical composition and application thereof
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The invention relates to propynamide derivatives shown in a formula I as well as pharmaceutically acceptable salt and preparation method thereof, a composition containing one or more of the compounds, and an application of the compounds to treatment of tu
- -
-
Paragraph 0055; 0057; 0058
(2019/10/15)
-
- NOVEL CLASS OF QUINOLONE HETEROCYCLIC AROMATIC MOLECULES FOR CANCER TREATMENT
-
The invention is directed to new class of quinolone heterocyclic aromatic molecules (Renotinibs) and their use in the treatment of cancer, in particular, cancer that harbor abnormal human epidermal growth factor receptors (EGFRs).
- -
-
Paragraph 0102
(2018/05/24)
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- COMPOUNDS USEFUL AS INHIBITORS OF ALCAT 1
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Inhibitors of ALCAT1 are described having the general formula: (I). These compounds offer a treatment for aging and age-related diseases.
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Page/Page column 104; 136
(2018/10/25)
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- BENZAMIDE OR BENZAMINE COMPOUNDS USEFUL AS ANTICANCER AGENTS FOR THE TREATMENT OF HUMAN CANCERS
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The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not
- -
-
Paragraph 0683; 0684
(2017/01/26)
-
- Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance
-
Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWTphenotypic melanoma and BRafV600Ephenotypic colon cells. The western blot results for the Erk inhibition in human melanoma SK-Mel-2?cell lines showed I-41 inhibited the proliferation of SK-Mel-2?cell lines without paradoxical activation of Erk, which supported I-41 may become a good candidate compound to overcome the resistance of melanoma against the current BRafV600Einhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described.
- Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhi, Yanle,Zhang, Li,Mao, Tianxiao,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
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supporting information
p. 86 - 106
(2017/03/02)
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- IDH2 (isocitrate dehydrogenase 2) mutant inhibitor and application thereof
-
The invention relates to a compound of formula I shown in the description and its pharmaceutically salts, solvents and hydrates, as well as a pharmaceutical composition comprising the compound of formula I and application thereof as an IDH (isocitrate deh
- -
-
Paragraph 0231; 0232; 0233
(2017/08/09)
-
- Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine
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We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.
- Walter, Niklas M.,Wentsch, Heike K.,Bührmann, Mike,Bauer, Silke M.,D?ring, Eva,Mayer-Wrangowski, Svenja,Sievers-Engler, Adrian,Willemsen-Seegers, Nicole,Zaman, Guido,Buijsman, Rogier,L?mmerhofer, Michael,Rauh, Daniel,Laufer, Stefan A.
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supporting information
p. 8027 - 8054
(2017/10/18)
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- Potent Pan-Raf and Receptor Tyrosine Kinase Inhibitors Based on a Cyclopropyl Formamide Fragment Overcome Resistance
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While selective BRafV600E inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway. Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs). Based on the binding mode of I-01, analogues I-02-I-18 were designed and synthesized. The most promising compound I-16 potently inhibits all subtypes of Rafs with IC50 values of 3.49 (BRafV600E), 8.86 (ARaf), 5.78 (BRafWT), and 1.65 nM (CRaf), respectively. I-16 not only exhibit comparable antiproliferative activities with positive control compounds against HepG2, SW579, MV4-11, and COLO205 cell lines, but also suppress the proliferation of melanoma SK-MEL-2 harboring overexpressed BRafWT with IC50 values of 0.93 μM. The Western blot results for the ERK inhibition in human melanoma SK-MEL-2 cell lines show that I-16 inhibits the proliferation of SK-MEL-2 cell lines without paradoxical activation of ERK, which support the hypothesis that the inhibition of Pan-Raf and RTKs might be a tractable strategy to overcome the resistance of melanoma induced by the therapy with the current selective BRafV600E inhibitors.
- Zhang, Yanmin,Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
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p. 1439 - 1452
(2017/06/30)
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- Structure-based design of ester compounds to inhibit MLL complex catalytic activity by targeting mixed lineage leukemia 1 (MLL1)–WDR5 interaction
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WDR5 is an essential protein for enzymatic activity of MLL1. Targeting the protein–protein interaction (PPI) between MLL1 and WDR5 represents a new potential therapeutic strategy for MLL leukemia. Based on the structure of reported inhibitor WDR5-0103, a
- Li, Dong-Dong,Wang, Zhi-Hui,Chen, Wei-Lin,Xie, Yi-Yue,You, Qi-Dong,Guo, Xiao-Ke
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p. 6109 - 6118
(2016/11/09)
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- 2-Amino-1-phenyl-pyrrolo[3,2-b]quinoxaline-3-carboxamide derivates
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The invention relates to compound characterized by a general formula (1), wherein n of R1n is 0, 1, 2, 3 or 4, in particular n of R1n is 0 or 1, and each R1 independently from any other R1
- -
-
Paragraph 0148
(2015/11/16)
-
- The flocculated acryloyldimethyltauric molecule ligand
-
Provided are certain benzothiazole, imidazothiazole, imidazopyrimidine and imidazopyridine compounds, including, for example: formula (I) and pharmaceutically and physiologically acceptable salts, hydrates, and solvates thereof. Such compounds can be used as diagnostic ligands or labels of tau protein and PHF.
- -
-
Paragraph 0581
(2016/10/08)
-
- Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties
-
The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB2R) of the end
- Nimczick, Martin,Pemp, Daniela,Darras, Fouad H.,Chen, Xinyu,Heilmann, Joerg,Decker, Michael
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supporting information
p. 3938 - 3946
(2014/08/18)
-
- Pyrrolo[3,2-b ]quinoxaline derivatives as types I1/2 and II Eph tyrosine kinase inhibitors: Structure-based design, synthesis, and in vivo validation
-
The X-ray crystal structures of the catalytic domain of the EphA3 tyrosine kinase in complex with two type I inhibitors previously discovered in silico (compounds A and B) were used to design type I1/2 and II inhibitors. Chemical synthesis of a
- Unzue, Andrea,Dong, Jing,Lafleur, Karine,Zhao, Hongtao,Frugier, Emilie,Caflisch, Amedeo,Nevado, Cristina
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supporting information
p. 6834 - 6844
(2014/10/15)
-
- Structure-activity relationship studies and biological characterization of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase inhibitors
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The structure-activity relationship (SAR) study of two chemotypes identified as inhibitors of the human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (HPGD, 15-PGDH) was conducted. Top compounds from both series displayed potent inhibition (IC50 2 production in A549 lung cancer and LNCaP prostate cancer cells.
- Duveau, Damien Y.,Yasgar, Adam,Wang, Yuhong,Hu, Xin,Kouznetsova, Jennifer,Brimacombe, Kyle R.,Jadhav, Ajit,Simeonov, Anton,Thomas, Craig J.,Maloney, David J.
-
supporting information
p. 630 - 635
(2014/01/23)
-
- Discovery, synthesis and biological evaluation of cycloprotoberberine derivatives as potential antitumor agents
-
A series of new 1,13-cycloprotoberberine derivatives defined through variations at the 9-position were designed, synthesized and evaluated for their cytotoxicities in human HepG2 (hepatoma), HT1080 (fibrosarcoma) and HCT116 (colon cancer) cells. The preliminary structure-activity relationship (SAR) revealed that the replacement of 9-methoxyl with an ester moiety might significantly enhance the antiproliferative activity in vitro. Notably, compound 7f demonstrated equipotent cytotoxicity activity against breast cancer MCF-7 (parent) and doxorubicin (DOX)-resistant MCF-7 (MCF-7/ADrR) cells, indicating a mode of action different from that of DOX. Further mechanism study showed that 7f significantly inhibited activity of DNA topoisomerase I (Top I) and Top II. G2/M phase arrest and tumor cell growth reduction was observed thereafter. Thus, we consider cycloprotoberberine analogues to be a new family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.
- Li, Yang-Biao,Zhao, Wu-Li,Wang, Yan-Xiang,Zhang, Cai-Xia,Jiang, Jian-Dong,Bi, Chong-Wen,Tang, Sheng,Chen, Ru-Xian,Shao, Rong-Guang,Song, Dan-Qing
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p. 463 - 472
(2013/10/01)
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- AGENT FOR TREATMENT OR PREVENTION OF DISEASES ASSOCIATED WITH ACTIVITY OF NEUROTROPHIC FACTORS
-
A compound depicted by the formula below, or a pharmaceutically acceptable salt or solvate thereof. wherein, R1 represents (1) a C3-6 alkyl group,(2) a C1-6 alkyl group substituted with one or more substituent group(s) sel
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-
Page/Page column 82-83
(2012/04/17)
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- TRICYCLIC INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
-
This invention relates to tricycle I and its therapeutic and prophylactic uses, wherein the variables C1, C2, Z1, Z2, Q, J, R1, and R3 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 41
(2012/06/01)
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- Exploration of the chemical space of novel naphthalene-sulfonamide and anthranilic acid-based inhibitors of penicillin-binding proteins
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Penicillin-binding proteins are a well established, validated and still a very promising target for the design and development of new antibacterial agents. Based on our previous discovery of several noncovalent small-molecule inhibitor hits for resistant
- Sosic, Izidor,Turk, Samo,Sinreih, Masa,Trost, Nusa,Verlaine, Olivier,Amoroso, Ana,Zervosen, Astrid,Luxen, Andre,Joris, Bernard,Gobec, Stanislav
-
scheme or table
p. 380 - 388
(2012/09/05)
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- PHENYL-THIAZOLYL INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to phenyl thiazole I and its therapeutic and prophylactic uses, wherein the variables Rz, Q, J, R1, R3, R5, R6, and R7 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 25
(2012/12/13)
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- COMPOSITIONS AND METHODS FOR MODULATING A KINASE
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The invention relates to compounds and methods for modulating one or more components of a kinase signaling cascade
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Page/Page column 202; 203
(2013/02/27)
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- Efficient and diversity-oriented total synthesis of Riccardin C and application to develop novel macrolactam derivatives
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Riccardin C (RC, 1) is a macrocyclic bis(bibenzyl) natural product exhibiting remarkable biological activity as a nuclear liver X receptors (LXRs) ligand and a lipid metabolism mediator. RC is expected to be a lead compound to develop drugs for atherosclerotic diseases, and therefore exploiting diversity-oriented synthesis of RC is a promising approach to drug discovery. In this paper, we report novel total synthesis of RC (7.4% overall yield in 16 steps) by using the intramolecular SNAr reaction as key cyclization reaction. This is the first example of efficient macrocyclization using 3-nitro-4-fluorostilbene as an electrophile. The methodology could be applied to synthesize novel lactam analogs of RC. The diversity-oriented synthesis of RC is versatile method for the synthesis of various types of bis(bibenzyl) natural products and their derivatization.
- Iwashita, Masazumi,Fujii, Shinya,Ito, Shigeru,Hirano, Tomoya,Kagechika, Hiroyuki
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body text
p. 6073 - 6082
(2011/08/22)
-
- Method for Producing Sulfonamides
-
The invention relates to methods for producing sulfonamides of formula I, wherein the variables have the designations cited in the description, by reacting m-nitro-benzoic acid chlorides of formula II with aminosulfons of formula III, under the influence
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Page/Page column 17
(2010/09/17)
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- Structure-activity relationship of new anti-tuberculosis agents derived from oxazoline and oxazole benzyl esters
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During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7?μM, average). Herein we
- Moraski, Garrett C.,Chang, Mayland,Villegas-Estrada, Adriel,Franzblau, Scott G.,M?llmann, Ute,Miller, Marvin J.
-
experimental part
p. 1703 - 1716
(2010/06/19)
-
- 3H-IMIDAZO [4, 5 -C] PYRIDINE- 6 -CARBOXAMIDES AS ANTI- INFLAMMATORY AGENTS
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The present invention relates to compounds of general formula (I) in which A, L, M, Q2, Q3, Q4, R1, R5, Ra, Rb, Rc, W, X, Y, Z1, Z2, Z3 are defined in the description, the salts thereof, particularly the physiologically acceptable salts thereof. The compounds are of potential utility in the treatment and/or prevention of inflammatory diseases and associated conditions, in particular, in the treatment and/or prevention of pain. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to their preparation.
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Page/Page column 117
(2010/09/18)
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- INSECTICIDAL COMPOUNDS
-
A compound of formula (I) wherein A1, A2, A3, A4, G1, G2, R1, R2, R3, R4, Q1, Y1, Y2, Y3 and Y4
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Page/Page column 33
(2009/05/28)
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- COMPOSITION FOR PREVENTING HARMFUL ORGANISMS
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There is a harmful organism that cannot be controlled or is difficult to be controlled with the use of a single agent of a compound represented by the general formula (1) according to the invention, an insecticide, a miticide or a fungicide. Accordingly, an object of the invention is to provide a composition for preventing harmful organisms for efficiently controlling such a harmful organism. That is, the invention is directed to a composition for preventing harmful organisms, characterized by comprising the compound represented by the general formula (1) and other insecticides, miticides or fungicides as active ingredients, wherein, in the formula, A1, A2, A3 and A4 independently represent a carbon atom, a nitrogen atom or an oxidized nitrogen atom, G1 and G2 independently represent an oxygen atom or a sulfur atom; R1 and R2 independently represent a hydrogen atom or a C1 to C4 alkyl group; Xs may be the same or different and represent a hydrogen atom, a halogen atom or a trifluoromethyl group; Q1 represents a substituent such as a phenyl group or a heterocyclic group; and Q2 represents a substituent such as a phenyl group or a heterocyclic group.)
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Page/Page column 94
(2009/07/10)
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- Discovery and optimization of antibacterial AccC inhibitors
-
The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohe
- Cheng, Cliff C.,Shipps Jr., Gerald W.,Yang, Zhiwei,Sun, Binyuan,Kawahata, Noriyuki,Soucy, Kyle A.,Soriano, Aileen,Orth, Peter,Xiao, Li,Mann, Paul,Black, Todd
-
scheme or table
p. 6507 - 6514
(2010/05/17)
-
- INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE
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Inhibitors of poly(ADP-ribose)polymerase, ways to make them and methods of treating patients using them are disclosed.
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Page/Page column 31
(2008/12/06)
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- Benzoylurea derivatives as a novel class of antimitotic agents: Synthesis, anticancer activity, and structure-activity relationships
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Forty-six new compounds were synthesized on the basis of our knowledge of the 3-haloacylamino benzoylurea (HBU) series. Structure-activity relationship (SAR) analysis indicates that (i) the configuration of the chiral center in 1 (JIMB01) is not indispensable for the activity, (ii) the phenyl ring is essential, and (iii) a substitution at the 6-position of the phenyl ring with a halogen enhances the activity. Among the analogues, 11e and 14b bearing 6-fluoro substitution showed potent activities against nine human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), PC-3 (prostate cancer), DND-1A(melanoma), LOVO (colon cancer), and MIA Paca (pancreatic cancer) with IC50 values between 0.01 and 0.30 μM. 14b inhibited human hepatocarcinoma by 86% in volume in nude mice. The mechanism of 14b is to inhibit microtubule assembly, followed by the M-phase arrest, bcl-2 inactivation, and then apoptosis. We consider 14b promising for further anticancer investigation.
- Song, Dan-Qing,Wang, Yan,Wu, Lian-Zong,Yang, Peng,Wang, Yue-Ming,Gao, Li-Mei,Li, Yan,Qu, Jing-Rong,Wang, Yong-Hong,Li, Ying-Hong,Du, Na-Na,Han, Yan-Xing,Zhang, Zhi-Ping,Jiang, Jian-Dong
-
experimental part
p. 3094 - 3103
(2009/04/06)
-
- Design and synthesis of highly sensitive fluorogenic substrates for glutathione S-transferase and application for activity imaging in living cells
-
Here we report the development of fluorogenic substrates for glutathione S-transferase (GST), a multigene-family enzyme mainly involved in detoxification of endogenous and exogenous compounds, including drug metabolism. GST is often overexpressed in a variety of malignancies and is involved in the development of resistance to various anticancer drugs. Despite the medical significance of this enzyme, no practical fluorogenic substrates for fluorescence imaging of GST activity or for high-throughput screening of GST inhibitors are yet available. So, we set out to develop new fluorogenic substrates for GST. In preliminary studies, we found that 3,4-dinitrobenzanilide (NNBA) is a specific substrate for GST and established the mechanisms of its glutathionylation and denitration. Using these results as a basis for off/on control of fluorescence, we designed and synthesized new fluorogenic substrates, DNAFs, and a cell membrane-permeable variant, DNAT-Me. These fluorogenic substrates provide a dramatic fluorescence increase upon GST-catalyzed glutathionylation and have excellent kinetic parameters for the present purpose. We were able to detect nuclear localization of GSH/GST activity in HuCCT1 cell lines with the use of DNAT-Me. These results indicate that the newly developed fluorogenic substrates should be useful not only for high-throughput GST-inhibitor screening but also for studies on the mechanisms of drug resistance in cancer cells.
- Fujikawa, Yuuta,Urano, Yasuteru,Komatsu, Toru,Hanaoka, Kenjiro,Kojima, Hirotatsu,Terai, Takuya,Inoue, Hideshi,Nagano, Tetsuo
-
experimental part
p. 14533 - 14543
(2009/02/08)
-
- COMPOUNDS FOR INHIBITING KSP KINESIN ACTIVITY
-
The present invention provides compounds of Formula (I); wherein R, R1, R2, R3, and R4 are as defined herein. The present invention also provides compositions comprising these compounds that are useful for treating cellular proliferative diseases or disor
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-
Page/Page column 115-116
(2009/01/24)
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- ANTI-VIRAL COMPOUNDS
-
Compounds effective in inhibiting replication of Hepatitis C virus ("HCV") or other viruses are disclosed. This invention is also directed to compositions comprising such compounds, co-formulation or co-administration of such compounds with other anti-viral or therapeutic agents, processes and intermediates for the syntheses of such compounds, and methods of using such compounds for the treatment of HCV or other viral infections.
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Page/Page column 119; 170
(2010/11/27)
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- Design, synthesis, and biological activity of 5,10-dihydro-dibenzo[b,e][1, 4]diazepin-11-one-based potent and selective Chk-1 inhibitors
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A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the
- Wang, Le,Sullivan, Gerard M.,Hexamer, Laura A.,Hasvold, Lisa A.,Thalji, Reema,Przytulinska, Magdalena,Tao, Zhi-Fu,Li, Gaoquan,Chen, Zehan,Xiao, Zhan,Gu, Wen-Zhen,Xue, John,Bui, Mai-Ha,Merta, Philip,Kovar, Peter,Bouska, Jennifer J.,Zhang, Haiying,Park, Chang,Stewart, Kent D.,Sham, Hing L.,Sowin, Thomas J.,Rosenberg, Saul H.,Lin, Nan-Horng
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p. 4162 - 4176
(2008/02/13)
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- SUBSTITUTED [1,4]-DIAZEPANES AS CXCR3 ANTAGONISTS AND THEIR USE IN THE TREATMENT OF INFLAMMATORY DISORDERS
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CXCR3 inhibitors of formula are disclosed. Inhibition of CXCR3 activation is useful for treating disorders resulting from CXCR3 -associated T-cell mediated function, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and diabetes
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Page/Page column 24; 30; 32
(2008/06/13)
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- Identification and initial evaluation of 4-N-aryl-[1,4]diazepane ureas as potent CXCR3 antagonists
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The identification and evaluation of aryl-[1,4]diazepane ureas as functional antagonists of the chemokine receptor CXCR3 are described. Specific examples exhibit IC50 values of ~60 nM in a calcium mobilization functional assay, and dose-dependently inhibit CXCR3 functional response to CXCL11 (interferon-inducible T-cell α chemoattractant/I-TAC) as measured by T-cell chemotaxis, with a potency of approximately 100 nM.
- Cole, Andrew G.,Stroke, Ilana L.,Brescia, Marc-Raleigh,Simhadri, Srilatha,Zhang, Joan J.,Hussain, Zahid,Snider, Michael,Haskell, Christopher,Ribeiro, Sofia,Appell, Kenneth C.,Henderson, Ian,Webb, Maria L.
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p. 200 - 203
(2007/10/03)
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- AMIDE DERIVATIVES, PROCESS FOR PRODUCTION OF THE SAME, AND METHOD FOR APPLICATION THEREOF AS INSECTICIDE
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An object of the present invention is to provide a compound represented by Formula (1): wherein A1, A2, A3 and A4 each represent a carbon atom, a nitrogen atom or an oxidized nitrogen atom; R1 and R2 each represent a hydrogen atom, an optionally substituted alkyl group or an optionally substituted C1-C4 alkylcarbonyl group; G1 and G2 each represent an oxygen atom or a sulfur atom; X, which may be identical or different each other, represents a hydrogen atom, a halogen atom, a C1-C3 alkyl group or a trifluoromethyl group; n is an integer of 0 to 4; and Q1 represents an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted heterocyclic group; Q2 represents a phenyl group or heterocyclic group having one or more substituents, at least one of the substituent being any of a C1-C4 haloalkoxy group, a C2-C6 perfluoroalkyl group, a C1-C6 perfluoroalkylthio group, a C1-C6 perfluoroalkylsulfinyl group and a C1-C6 perfluoroalkylsulfonyl group, an insecticide comprising the compound as the active ingredient, and a process for preparation thereof.
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Page/Page column 163
(2010/11/24)
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- SUBSTITUTED HETEROCYCLES AND THEIR USE AS CHK1, PDK1 AND PAK INHIBITORS
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This invention relates to novel compounds of Formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds possess CHK1 kinase inhibitory activity, PDK1 inhibitory activity and Pak kinase inhibitory activity and are accordingly useful in the treatment and/or prophylaxis of cancer.
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Page/Page column 131
(2008/06/13)
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- Theoretical and experimental design of atypical kinase inhibitors: Application to p38 MAP kinase
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Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-
- McClure, Kim F.,Abramov, Yuriy A.,Laird, Ellen R.,Barberia, John T.,Cai, Weiling,Carty, Thomas J.,Cortina, Santo R.,Danley, Dennis E.,Dipesa, Alan J.,Donahue, Kathleen M.,Dombroski, Mark A.,Elliott, Nancy C.,Gabel, Christopher A.,Han, Seungil,Hynes, Thomas R.,LeMotte, Peter K.,Mansour, Mahmoud N.,Marr, Eric S.,Letavic, Michael A.,Pandit, Jayvardhan,Ripin, David B.,Sweeney, Francis J.,Tan, Douglas,Tao, Yong
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p. 5728 - 5737
(2007/10/03)
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- METHODS OF TREATING ACUTE INFLAMMATION IN ANIMALS WITH p38 MAP KINASE INHIBITORS
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The present invention provides methods for treating animals having acute inflammatory conditions, including mastitis, by administering at least one p38 MAP kinase inhibitor. The present invention also provides methods for enhancing milk production and red
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Page/Page column 14-15; 18
(2010/02/12)
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- PYRROLOTRIAZINE KINASE INHIBITORS
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The present invention provides compounds of formula I, (I) and pharmaceutically acceptable salts thereof. The formula I compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as ant
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- AZOLECARBOXAMIDE HERBICIDES
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Compounds of Formula (I), and their N-oxides and agriculturally suitable salts, are disclosed which are useful for controlling undesired vegetation, wherein J is (J-1), (J-2,(J-3), (J-4), (J-5), (J-6), (J-7), (J-8) and R1a, R1b, R1c, R2a, R2b, R3, R4, R05, T, U, W, Y and Z are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula (I) and a method for controlling undesired vegetation which involves contacting the vegetation or its environment with an effective amount of a compound of Formula (I). Also disclosed are mixtures and compositions comprising a herbicidally effective amount of a compound of Formula (Iz) wherein J, R1a, R1b, R1c, R2a, R2b, R3, R4, R05, T, U, W, Y and Z are as defined in the disclosure; and an effective amount of another herbicide or herbicide safener. Also disclosed is a method for selectively controlling undesired vegetation in a crop that involves contacting the locus of a crop with an effective amount of a compound of Formula (Iz) and a effective amount of a safener.
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- 3-QUINOLINE-2-(1H)-YLIDENEINDOLIN-2-ONE DERIVATIVES
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There is provided medicaments, particularly a vascular endothelial growth factor (VEGF) inhibitor which is useful as a therapeutic drug for solid tumors, diabetic retinopathy and the like diseases in which angiogenesis is taking a role. That is, since a novel 3-quinolin-2(1H)-ylideneindolin-2-one derivative or a salt thereof has good VEGF inhibitory action, angiogenesis inhibitory action and anti-tumor action, it is useful as ideal VEGF inhibitor, angiogenesis inhibitor and anti-tumor agent.
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- Viral polymerase inhibitors
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An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: wherein R1 is selected from: H, haloalkyl, (C1-6)alkyl, (C2-6)alkenyl, (C3-7)cycloalkyl, (C2-6)alkynyl, (C5-7)cycloalkenyl, 6 or 10-membered aryl, Het all optionally substituted; R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C6-10)bicycloalkyl, 6- or 10-membered aryl, or Het all optionally substituted; B is N or CR5, wherein R5 is H, halogen, haloalkyl, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; X is N or CR5; D is N or CR5; each of Y1 and Y2 is independently O or S; Z is O, N, or NRz wherein Rz is H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; R3 and R4 are each independently H, (C1-6)alkyl, first (C3-7)cycloalkyl or 6- or 10-membered aryl, Het (C1-6)alkyl-6- or 10-membered aryl, (C1-6)alkyl-Het; or each R3 and R4 are independently covalently bonded together to form second (C3-7)cycloalkyl, or heterocycle, all optionally substituted; or when Z is N, either R3 or R4 are independently covalently bonded thereto to form a nitrogen-containing heterocycle; R7 is H, (C1-6 alkyl), (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; or R7 is covalently bonded to either of R3 or R4 to form a heterocycle; A is (C1-6) alkyl-CONHR8 wherein R8 is-6- or 10-membered aryl, or Het; or A is a 6- or 10-membered aryl, or Het said aryl or Het being optionally substituted; or a salt or a derivative thereof; such compounds being potent inhibitors of HCV NS5B polymerase.
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