- Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors
-
The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 μM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.
- Machado, Vera A.,Peixoto, Daniela,Costa, Raquel,Froufe, Hugo J.C.,Calhelha, Ricardo C.,Abreu, Rui M.V.,Ferreira, Isabel C.F.R.,Soares, Raquel,Queiroz, Maria-Jo?o R.P.
-
-
Read Online
- NITROGEN-CONTAINING FUSED CYCLIC COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF
-
The present invention relates to a nitrogen-containing fused ring compound, a preparation method and use thereof. Specifically, the present invention relates to a compound having the structure of Formula (X), a stereoisomer, tautomer or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate thereof, or a stable isotope derivative, metabolite or prodrug thereof. The compound of the invention may have the structure of Formula (I) or Formula (II). These compounds are useful for the treatment of an abnormal cell proliferation disease (e.g., cancer). ????????R-L-R3?????(X)
- -
-
-
- BIOMARKER-BASED THERAPEUTIC COMPOSITION
-
The present invention provides an anticancer agent for treating a patient who is resistant to a protein kinase inhibitor, the anticancer agent comprising, as an active ingredient, a thienopyridine derivative compound or a pharmaceutically acceptable salt thereof. Here, the patient may be a patient carrying active RON. In addition, the patient may be a patient carrying normal KRAS. In addition, the anticancer agent may be applied to a patient who is resistant to an EGFR inhibitor. In particular, the anticancer agent may be usefully used to treat a patient who is resistant to the therapeutic agent cetuximab.
- -
-
Paragraph 0077-0078
(2021/05/13)
-
- Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
-
In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
- Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
-
-
- Polysubstituted quinolone compounds, and preparation method and use thereof
-
The invention provides polysubstituted quinolone compounds, and a preparation method and a use thereof, and concretely provides a polysubstituted quinolone compound represented by formula I, and optical isomers, pharmaceutically acceptable salts or solvates thereof. All groups in the formula I are defined in the description. The quinolone compound has excellent c-Met inhibition activity, and can be used for treating c-Met activity or expression level corrected diseases.
- -
-
Paragraph 0262; 0263; 0264
(2017/09/19)
-
- Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
-
The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth.
- -
-
Page/Page column 361
(2016/04/26)
-
- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
-
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or a receptor tyrosine kinase (RTK) in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or an RTK in a subject. In yet another aspect, a method of inhibiting phosphorylation of Akt (S473) in a cell is set forth.
- -
-
Page/Page column 75
(2015/02/19)
-
- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
-
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
- -
-
Paragraph 00641
(2014/10/04)
-
- ANTI-INFLAMMATORY COMPOUND HAVING INHIBITORY ACTIVITY AGAINST MULTIPLE TYROSINE KINASES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
-
The present invention is for the anti-inflammatory compounds that have an inhibitory activity against protein tyrosine kinases and their pharmaceutical composition(s) containing the compound as the active ingredient. Since the compounds of the present invention can inhibit multiple protein kinases associated with inflammatory diseases and immune disorders, they are useful for their prevention or treatment.
- -
-
Paragraph 0281; 0286; 0287
(2013/03/28)
-
- SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS
-
Disclosed are azaindazole compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O and Y is N; or X is S and Y is CH; Z is CR2 or N; Q is a heteroaryl; and R1 is defined herein. Also disclosed are methods of using such compounds in the treatment of at least one CYP17 associated condition, such as, for example, cancer, and pharmaceutical compositions comprising such compounds.
- -
-
Paragraph 00323; 00324
(2013/04/13)
-
- NEW COMPOUNDS
-
There is provided compounds of formula I, wherein R1, R2a, R2b, R2c, X, Y, Z, R3 and ring A/B have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. PI3-K, particularly class I PI3K, PIM family kinase and/or mTOR) is desired and/or required, and particularly in the treatment of cancer. The invention also relates to combinations containing such compounds.
- -
-
Page/Page column 144; 99
(2012/12/13)
-
- HETEROARYLS AND THEIR USE AS PI3K INHIBITORS
-
This invention provides compounds of formula (IA) or (IB): wherein R1, R2, G1 and HY are as described in the specification. The compounds are inhibitors of PI3K and/or mTor and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.
- -
-
Page/Page column 334
(2010/08/18)
-
- PROCESSES AND INTERMEDIATES FOR PREPARING FUSED HETEROCYCLIC KINASE INHIBITORS
-
The invention relates to processes and intermediates for manufacturing fused heterocyclic-type kinase inhibitor compounds, such as thienopyridine-based compounds, and to processes and intermediates for preparing intermediates that are useful in the manufacture of fused heterocyclic-type kinase inhibitor compounds, particularly at an industrial level The processes are aimed at ultimately forming compounds of the formula (A) where M is thieno[3,2,b]pyridinyl as shown, the group D is a ring or ring system, preferably pyridine, and the group Z, Ar, and G are as defined herein Such compounds can act to inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signalling, for example, the inhibition of VEGF receptor signalling and HGF receptor signalling.
- -
-
Page/Page column 93; 94
(2009/04/25)
-
- 2-AMINOPYRIDINE DERIVATIVES AS GLUCOKINASE ACTIVATORS
-
Provided are compounds having the Formula (I) or salts thereof, wherein: L is O, S, SO, SO2, CHOH, C(O), or CH2; D2 is CR12 or N; R2 is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocyclyl (optionally substituted with oxo), wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are monocyclic or bicyclic and are further optionally substituted with one or more groups independently selected from C1-C6 alkyl, F, Cl, Br, I, CF3, CN, OR6, C(=O)R6, C(=O)OR6, O(CH2)nC(=O)OR6, C(=O)NR6R7, NO2 and (1-6C alkyl)OR6; R3 is H, Br, OR6, SR6, C(O)OR6, C(O)NR6R7, C(O)R6, heteroaryl, or C1-C6 alkyl substituted with one or more groups independently selected from Vn-aryl, Vn-OR6, Vn- C(=O)OR6 and Vn-NR6R7; R11 is H or Cl; and R13 is N-(1 -6C alkanoyl)piperidin-4-yl; that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.
- -
-
Page/Page column 42
(2008/12/07)
-
- Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases
-
A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC50 values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.
- Claridge, Stephen,Raeppel, Franck,Granger, Marie-Claude,Bernstein, Naomy,Saavedra, Oscar,Zhan, Lijie,Llewellyn, David,Wahhab, Amal,Deziel, Robert,Rahil, Jubrail,Beaulieu, Normand,Nguyen, Hannah,Dupont, Isabelle,Barsalou, Annie,Beaulieu, Carole,Chute, Ian,Gravel, Serge,Robert, Marie-France,Lefebvre, Sylvain,Dubay, Marja,Pascal, Roussen,Gillespie, Jeff,Jin, Zhiyun,Wang, James,Besterman, Jeffrey M.,MacLeod, A. Robert,Vaisburg, Arkadii
-
p. 2793 - 2798
(2008/12/21)
-
- Inhibitors of VEGF receptor and HGF receptor signaling
-
The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions
- -
-
Page/Page column 57
(2010/11/25)
-
- Heterobicyclic thiophene compounds and methods of use
-
Compounds of Formula I and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula I and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
- -
-
Page/Page column 50-51
(2008/06/13)
-
- COMPOUND HAVING TGF-BETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
-
The present invention provides compounds of formula (I) or compounds of formula (II) and pharmaceutically acceptable salts or solvates thereof. An objective of the present invention is to provide compounds having TGF2 inhibitory activity.
- -
-
Page/Page column 50-51
(2010/11/24)
-
- SUBSTITUTED AMIDE DERIVATIVES AS PROTEIN KINASE INHIBITORS
-
Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
- -
-
-
- INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING
-
The invention relates to the inhibition of vascular endothelial growth factor (VEGF) receptor signaling and hepatocyte growth factor (HGF) receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions
- -
-
Page/Page column 50; 56
(2010/02/15)
-
- Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity
-
Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.
- Munchhof, Michael J.,Beebe, Jean S.,Casavant, Jeffery M.,Cooper, Beth A.,Doty, Jonathan L.,Higdon, R. Carla,Hillerman, Stephen M.,Soderstrom, Catherine I.,Knauth, Elisabeth A.,Marx, Matthew A.,Rossi, Ann Marie K.,Sobolov, Susan B.,Sun, Jianmin
-
-
- Cross-coupling methods for the large-scale preparation of an imidazole - Thienopyridine: Synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl] -(2-methyl-1H-indol-5-yl)-amine
-
The multihundred-gram synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl] -(2-methyl-1H-indol-5-yl)-amine (1) is described utilizing a Stille cross-coupling of an iodothienopyridine (3) with 5-(tributylstannyl)-1-methylimidazole (11). Several cross-coupling methods were evaluated for the conversion of thienopyridine 3 to imidazole - thienopyridine 2, but only two were effective: the Stille coupling and a Negishi cross-coupling of the organozinc reagent derived from 2-(tertbutyldimethylsilyl)-1-methylimidazole and iodothienopyridine (3). The latter procedure worked well on laboratory scale (50 g), but was capricious upon scale-up. The issues with scale-up of an organostannane reagent are discussed, including control and analysis of organotin levels.
- Ragan,Raggon,Hill,Jones,McDermott,Munchhof,Marx,Casavant,Cooper,Doty,Lu
-
p. 676 - 683
(2013/09/05)
-
- BENZAMIDE DERIVATIVES USEFUL AS HISTONE DEACETYLASE INHIBITORS
-
The invention concerns a compound of the formula (I) wherein Ring A is heterocyclyl; m is 0-4 and each R1 is a group such as hydroxy, halo, trifluoromethyl and cyano; R2 is halo and n is 0-2; and each R4 is a group such as hydroxy, halo, trifluromethyl and cyano; p is 0-4; and R3 is amino or hydroxy; or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by histone deacetylase
- -
-
Page/Page column 79
(2008/06/13)
-
- Thienopyrimidine and thienopyridine derivatives useful as anticancer agents
-
The invention relates to compounds of the formulas 1 and 2 and to pharmaceutically acceptable salts and hydrates thereof, wherein X1, R1, R2and R11are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formulas 1 and 2 and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formulas 1 and 2.
- -
-
-
- Chemistry of Thienopyridines. XXXIII. Synthetic Routes to 5- and 7-Substituted Thienopyridines from the N-Oxide
-
Thienopyridine (1) is oxidized to N-oxide 1a by means of m-chloroperoxybenzoic acid (83percent).Compound 1a forms adducts with hydrogen chloride and picric acid and gives ring substitution alpha or gamma to the heteronitrogen atom.Thus, 1a plus nitric and sulfuric acids produces the 7-nitro-N-oxide 1m (63percent), or plus phosphorus oxychloride gives a mixture of 5-chloro and 7-chloro (1j) derivatives of 1.Compound 1m is convertible into a variety of other derivatives of 1, viz 7-chloro-N-oxide, 1j, 7-bromo-N-oxide, 7-nitro and 7-amino. 5-Cyano-1, formed from 1a, is, in turn, transformed into a methyl imidate (93percent), cyclic amidines, and a 5-tetrazolyl-1 (91percent).These results confirm the prediction that 1a, thienopyridine-4-oxide and quinoline 1-oxide should exhibit closely similar (i.e. analogous) chemical reactions.
- Klemm, L. H.,Louris, John N.,Boisvert, William,Higgins, Clay,Muchiri, Daniel R.
-
p. 1249 - 1252
(2007/10/02)
-
