- Development of a p38α-selective radioactive probe for qualitative diagnosis of cancer using SPECT
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Objective: p38 mitogen-activated protein (MAP) kinase (p38α) has drawn attention as a new target molecule for the treatment and diagnosis of cancer, and its overexpression and activation have been reported in various types of cancer. In this study, a single photon emission computed tomography (SPECT) imaging probe of p38α was developed to noninvasively image p38α activity for effective qualitative diagnosis of cancer. Methods: Pyrrolepyridine derivatives, m-YTM and p-YTM, were designed and synthesized based on the structure of the p38α-selective inhibitor. Radioactive iodine-labeled m-YTM, [125I]m-YTM, was synthesized because m-YTM greatly inhibited the phosphorylation of p38α upon examining the inhibitory effects of the compounds. After investigating the binding affinity of [125I]m-YTM to the recombinant p38α, a saturation binding experiment using activated p38α and inactive p38α was performed to determine the binding site. Uptake of [125I]m-YTM into various cancer cell lines was investigated, and the pharmacokinetics was evaluated using tumor-bearing mice. Results: The inhibitory activity of m-YTM was approximately 13 times higher than that of SB203580, a p38α-selective inhibitor. The binding site of [125I]m-YTM was estimated to be the p38α activating site, similar to that of SB203580, because the [125I]m-YTM bound strongly to both activated p38α and inactive p38α. Various different cancer cells incorporated [125I]m-YTM; however, its accumulation was significantly reduced by treatment with SB203580. Pharmacokinetics study of [125I]m-YTM in B-16 tumor-bearing mice was examined which revealed high accumulation of radioactivity in tumor tissues. The ratios of radioactivity in the B-16 tumor to that in blood were 3.1 and 50 after 1 and 24?h, respectively. The ratio of radioactivity in the tumor to that in blood in the tumor-bearing mice generated using other cancer cell lines was also ≥ 1 at 1?h after the administration of the probe. Conclusions: This study suggests that [123I]m-YTM has potential as a p38α imaging probe effective for various cancer types.
- Hirata, Masahiko,Yao, Tatsuma,Fujimura, Shigeaki,Kanai, Yasukazu,Yoshimoto, Mitsuyoshi,Sato, Takaji,Ohmomo, Yoshiro,Temma, Takashi
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p. 333 - 343
(2019/05/10)
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- MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
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Hydantoin based compounds useful as inhibitors of matrix metalloproteinases (MMPs), particularly macrophage elastase (MMP-12) are described. Also described are related compositions and methods of using the compounds to inhibit MMP-12 and treat diseases mediated by MMP-12, such as asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.
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Paragraph 0609-0610
(2019/12/02)
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- Discovery of the fibrinolysis inhibitor AZD6564, acting via interference of a protein-protein interaction
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A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.
- Cheng, Leifeng,Pettersen, Daniel,Ohlsson, Bengt,Schell, Peter,Karle, Michael,Evertsson, Emma,Pahlén, Sara,Jonforsen, Maria,Plowright, Alleyn T.,Bostr?m, Jonas,Fex, Tomas,Thelin, Anders,Hilgendorf, Constanze,Xue, Yafeng,Wahlund, G?ran,Lindberg, Walter,Larsson, Lars-Olof,Gustafsson, David
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supporting information
p. 538 - 543
(2014/06/09)
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- Discovery of (S)-1-(1-(Imidazo[1,2- a ]pyridin-6-yl)ethyl)-6-(1-methyl-1 H -pyrazol-4-yl)-1 H -[1,2,3]triazolo[4,5- b ]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal-Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer
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HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.
- Jia, Hong,Dai, Guangxiu,Weng, Jianyang,Zhang, Zhulin,Wang, Qing,Zhou, Feng,Jiao, Longxian,Cui, Yumin,Ren, Yongxin,Fan, Shiming,Zhou, Jinghong,Qing, Weiguo,Gu, Yi,Wang, Jian,Sai, Yang,Su, Weiguo
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supporting information
p. 7577 - 7589
(2014/12/11)
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- HETEROCYCLIC COMPOUND AND H1 RECEPTOR ANTAGONIST
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A heterocyclic compound useful as an antiallergic agent is provided. A compound represented by the following formula (1) or a salt thereof: wherein the ring A is a homocyclic or heterocyclic ring; the ring B is a heterocyclic ring which contains G and nitrogen atom N as constituent atoms thereof, wherein G is CH or N; R1 is a carbonyl group or an alkylene group; R2a and R2b are an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group; X is an oxygen atom or a sulfur atom; Z is a hydroxyl group, an alkoxy group, a cycloalkyloxy group, an aryloxy group, an aralkyloxy group, an amino group, or an N-substituted amino group; and n is 0 or 1; with the proviso that when the ring A is a benzene ring or when the ring B is a piperazine ring, R1 is an alkylene group which may have a substituent.
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Paragraph 0262; 0263; 0264
(2013/04/13)
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- CERTAIN TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES, COMPOSITIONS THEREOF AND METHODS OF USE THEREFOR
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Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.
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Page/Page column 27
(2012/10/08)
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- CERTAIN TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES, COMPOSITIONS THEREOF AND METHODS OF USE THEREFOR
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Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.
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Page/Page column 43
(2011/07/30)
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- ISOXAZOL-3(2H)-ONE ANALOGS AS THERAPEUTIC AGENTS
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or a pharmaceutically suitable salt thereof, wherein, R1 and R2 independently are hydrogen, deuterium, aryl, hetero aryl, C1-C8 alkyl, optionally being substituted with one or more substituents independently being R3,R3 is an aryl, hetero aryl, fluorine(s), a C1-C6 alkyl containing one or more fluorine, a C1-C6 alkyl containing one or more deuterium, a C1-C6 alkyl containing hydroxy, the aryl and heteroaryl optionally being substituted with one or more halogen, a fluorinated alkoxy, a fluorinated alkyl, a sulfonyl, one or more deuterium, a C1-6 alkyl, a C1-6 alkoxy, a nitrile,or R3 is a C1-6 alkyl optionally substituted with one or more of the following groups: COOR4, OCOR4, CONR5R6, NR5COR6, OR4;wherein, R4 is a C1-10 alkyl optionally substituted with one or more fluorine, deuterium, alkoxy, arylcarboxylate, alkyl carboxylate;R5 and R6 are independently selected from hydrogen, alkyl or they may together form a 4-8 membered carbon ring;or R1 and R2 form a 3-10 membered carbon ring optionally comprising O or N and optionally substituted with a C1-10 alkyl or aryl, hetero aryl optionally substituted with R3.
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Page/Page column 14
(2010/11/03)
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- A new photolabile protecting group for release of carboxylic acids by visible-light-induced direct and mediated electron transfer
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(Chemical Equation Presented) A new aqueous-compatible photoinduced electron transfer based photolabile protecting group has been developed for the release of carboxylic acids. The reduction potential of this group is more positive than previous systems,
- Borak, J. Brian,Falvey, Daniel E.
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supporting information; experimental part
p. 3894 - 3899
(2009/10/02)
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- 2-Pyrimidinyl Pyrazolopyridine Erbb Kinase Inhibitors
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The present invention provides 2-pyrimidinyl pyrazolopyridine compounds, compositions containing the same, as well as processes for the preparation and their use as pharmaceutical agents.
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Page/Page column 86
(2008/06/13)
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- PYRAZINE DERIVATIVES USEFUL AS ADENOSINE RECEPTOR ANTAGONISTS
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The present invention provides a compound of formula (I) wherein: A represents an optionally substituted monocyclic or polycyclic aryl or heteroaryl group B represents an optionally substituted monocyclic nitrogen-containing heteroaryl group ; and either a) R1 and R2 represent hydrogen or specified substituents, or b) R2, R1 and the -NH- group to which R1 is attached, form a moiety selected from the moiety of formulae (IIa) and (IIb): (IIa) These compounds are useful as antagonists of the A2B receptor, for instance in the treatment of asthma.
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Page/Page column 57-58
(2008/06/13)
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- MODULATORS OF HCV REPLICATION
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The present invention is directed to the use of certain 2,4,5-trisubstituted imidazole derivatives in modulating the replication of Hepatitis C virus RNA and/or virus production in cells.
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Page/Page column 8; 9
(2008/06/13)
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- NOVEL INDOLE DERIVATES AS FABP-4 INHIBITORS
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The present invention relates to novel compounds (I) wherein R0, R1, R2, R3, R4, R5, R6, R7, R8, A, B, n, X, and Y are as defined in the description and claims; and also to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament, which acts on the fatty acid binding protein FABP-4. The present invention relates to novel compounds (I) wherein R0, R1, R2, R3, R4, R5, R6, R7, R8, A, B, n, X, and Y are as defined in the description and claims; and also to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament, which acts on the fatty acid binding protein FABP-4.
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- 1-(Aromatic- or heteroaromatic-substituted)-3-(heteroaromatic substituted)-1,3-propanediones and uses thereof
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Certain 1-(aromatic- or heteroaromatic-substituted-3-(heteroaromatic substituted)-1,3-propanediones are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
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- TRIARYL SUBSTITUTED IMIDAZOLES AS GLUCAGON ANTAGONISTS
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2,4-Diaryl-5-pyridylimidazoles are glucagon antagonists. The compounds block the action of glucagon at its receptor. Thus, the compounds can be used in the prophylaxis or treatment of disease states in mammals mediated by elevated levels of glucagon. Exam
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- Regulation of stress-induced cytokine production by pyridinylimidazoles inhibition of CSBP kinase
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Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKα and ERK kinase activity is observed.
- Gallagher, Timothy F.,Seibel, George L.,Kassis, Shouki,Laydon, Jeffrey T.,Blumenthal, Mary Jane,Lee, John C.,Lee, Dennis,Boehm, Jeffrey C.,Fier-Thompson, Susan M.,Abt, Jeffrey W.,Soreson, Margaret E.,Smietana, Juanita M.,Hall, Ralph F.,Garigipati, Ravi S.,Bender, Paul E.,Erhard, Karl F.,Krog, Arnold J.,Hofmann, Glenn A.,Sheldrake, Peter L.,McDonnell, Peter C.,Kumar, Sanjay,Young, Peter R.,Adams, Jerry L.
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- 4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: Synthesis, activity at N-methyl-D-aspartic acid receptors, and anticonvulsant activity
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A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxyl acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay [(3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.
- Hutchison,Williams,Angst,De Jesus,Blanchard,Jackson,Wilusz,Murphy,Bernard,Schneider,Campbell,Guida,Sills
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p. 2171 - 2178
(2007/10/02)
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