- Structure-activity relationships for binding of 4-substituted triazole-phenols to macrophage migration inhibitory factor (MIF)
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Macrophage migration inhibitory factor (MIF) is a versatile protein that plays a role in inflammation, autoimmune diseases and cancers. Development of novel inhibitors will enable further exploration of MIF as a drug target. In this study, we investigated structure-activity relationships of MIF inhibitors using a MIF tautomerase activity assay to measure binding. Importantly, we notified that transition metals such as copper (II) and zinc (II) interfere with the MIF tautomerase activity under the assay conditions applied. EDTA was added to the assay buffer to avoid interference of residual heavy metals with tautomerase activity measurements. Using these assay conditions the structure-activity relationships for MIF binding of a series of triazole-phenols was explored. The most potent inhibitors in this series provided activities in the low micromolar range. Enzyme kinetic analysis indicates competitive binding that proved reversible. Binding to the enzyme was confirmed using a microscale thermophoresis (MST) assay. Molecular modelling was used to rationalize the observed structure-activity relationships. The most potent inhibitor 2d inhibited proliferation of A549 cells in a clonogenic assay. In addition, 2d attenuated MIF induced ERK phosphorylation in A549 cells. Altogether, this study provides insights in the structure-activity relationships for MIF binding of triazole-phenols and further validates this class of compounds as MIF binding agents in cell-based studies.
- Chen, Deng,Dekker, Frank J.,Fokkens, Marieke,Kok, Tjie,Poelarends, Gerrit J.,Proietti, Giordano,Xiao, Zhangping,van Merkerk, Ronald
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- Benzothiazolyl ureas are low micromolar and uncompetitive inhibitors of 17Β-HSD10 with implications to Alzheimer’s disease treatment
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Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson’s disease, or Alzheimer’s disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1–2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.
- Aitken, Laura,Benek, Ondrej,Chribek, Matej,Dolezal, Rafael,Gunn-Moore, Frank,Hrabinova, Martina,Hroch, Lukas,Jun, Daniel,Kralova, Vendula,Kuca, Kamil,Lycka, Antonin,Musilek, Kamil,Prchal, Lukas,Schmidt, Monika,Vinklarova, Lucie,Zemanova, Lucie
-
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- URACIL COMPOUND AS C-MET/AXL INHIBITOR
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Provided are a uracil compound represented by Formula (IV) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of the same. Also provided is a use thereof as a c-MET/AXL inhibitor in preparing a c-MET/AXL-inhibiting drug or a dr
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Paragraph 0187-0188
(2020/11/22)
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- Double-[...] compound and its method and use thereof
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The invention provides a type of substituted bicyclic pyrazolone compounds which can be used for inhibiting the activities of receptor tyrosine kinases especially the activities of Axl, Mer, c-Met and Ron kinases. The invention also provides medicine compositions comprising the type of compounds, and applications of the compound and the medicine compositions in drug preparation. The medicines can be used for preventing and treating proliferative diseases or reducing the severity of the diseases.
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Paragraph 0609; 0610
(2018/10/11)
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- SUBSTITUTED PYRAZOLONE COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted pyrazolone compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0445; 0446
(2015/02/19)
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- BICYLCIC PYRAZOLONE COMPOUNDS AND METHODS OF USE
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The present invention provides substituted bicyclic pyrazolone compounds, which are used to inhibit or modulate the activity of receptor tyrosine kinases, especially Axl, Mer, c-Met and Ron. The invention also provides pharmaceutical compositions comprising the compound disclosed herein, and a method of preventing, treating or lessening the severity of a proliferative disorder in a patient with the compounds or the pharmaceutical compositions disclosed herein.
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Paragraph 0295
(2015/11/16)
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- SUBSTITUTED PYRAZOLONE COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted pyrazolone compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0223
(2014/02/16)
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- Trifluoroacetic acid: An efficient catalyst for paal-knorr pyrrole synthesis and its deprotection
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In the present work, we demonstrated a simple and an efficient method for the condensation of substituted aryl/heteroaryl amines with acetonylacetone in the presence of trifluoro acetic acid to afford the corresponding 2,5-dimethyl-1-substitued pyrroles using Paal-Knorr synthesis in excellent yields. Trifluoroacetic acid was used under reflux condition for the deprotection of 2,5-dimethyl-1-substitued pyrroles to their corresponding substituted aryl/heteroaryl amines in moderate yields. 2,5-Dimethyl-1-substitued pyrrole were characterized by NMR and LC-MS. The yield of the compounds was found to be excellent.
- Venugopala, K. Narayanaswamy,Prasanna, Renuka T.,Odhav, Bharti
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p. 8685 - 8689
(2013/11/06)
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- New clicked full agonists of the estrogen receptor β
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A click chemistry approach was used to synthesize a series of 1,4-diaryl-substituted 1,2,3-triazoles designed to behave as estrogen receptor (ER) ligands. We studied their affinities for both receptors α and β, their agonist activities in a cell-based luciferase reporter assay and their effect on the proliferation of the hormone-dependent MCF-7 cell line. We found two compounds (3a and 3c) that behave as selective full agonists for ERβ at a 20 μM concentration, and one of them (3c) showed no proliferative effect on MCF-7 cells.
- Demkowicz, Sebastian,Filipiak, Kamila,Maslyk, MacIej,Ciepielski, Jakub,De Pascual-Teresa, Sonia,Martin-Santamaria, Sonsoles,De Pascual-Teresa, Beatriz,Ramos, Ana
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p. 3697 - 3706
(2013/04/10)
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- Clauson-kaas-type synthesis of pyrrolyl-phenols, from the hydrochlorides of aminophenols, in the presence of nicotinamide
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A facile Clauson-Kaas-type pyrrolyl-phenol synthesis has been achieved in the presence of nicotinamide, which is inexpensive and nontoxic. The starting material is aminophenol hydrochloride. This is advantageous in certain cases because it is the only isolatable form of the corresponding aminophenol.
- Chatzopoulou, Maria,Kotsampasakou, Eleni,Demopoulos, Vassilis J.
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p. 2949 - 2954
(2013/09/02)
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- MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO
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The present invention relates to compounds of Formula I and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.
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Page/Page column 168
(2012/11/07)
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- PHENOXYPROPANOL DERIVATIVES AND THEIR USE IN TREATING CARDIAC AND CARDIOVASCULAR DISEASES
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A compound of formula I-0, and its pharmaceutically acceptable salt or salts and physiologically hydrolysable derivatives in free form or salt form: wherein Z1 is C1-C4 linear or branched alkyl or alkenyl; R4 is selected from unsubstituted and substituted C3-C8 cycloalkyl, C1-C8 linear or branched alkyl, C2-5 alkenyl, C6-C10 heteroaryl or aryl, or C3-C8 heterocyclyl which may be part unsaturated, and combinations thereof; is linear C2-3 alkylene,; X1 is selected from NH and O; X2 is selected from unsaturated C and unsaturated S; and X3 is selected from NH and CH2; or one of X1 and X3 is a single bond; or X1 is O and X2 and X3 together are a single bond; and R7 is selected from oxo, F, Cl, Br, CN, NH2, NR92, NO2, CF3, OR9, COR9, OCOR9, COOR9, NR9COR9, CONR92 SO2NR92, NR9SO2R9; and R8 is selected from C1-5 alkyl, C1-5 alkoxyl, C2-5 alkenyl or alkynyl, C6-10) aryl and C3-8 cycloalkyl and combinations thereof, which may be unsubstituted or f urther substituted by one or more F, Cl, Br, CN, NH2, NR32, NO2, CF3; and R9 is selected from H and a group R8 as hereinbefore defined; n7 and n8 and the sum thereof are independently selected from zero and the whole number integer 1 to 4; processes for the preparation thereof, compositions and uses.
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Page/Page column 35
(2012/02/01)
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- PROCESSES AND INTERMEDIATES FOR PREPARING FUSED HETEROCYCLIC KINASE INHIBITORS
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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.
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Page/Page column 93; 94
(2009/04/25)
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- NOVEL COMPOUNDS
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The present invention relates to a class of substituted purine compounds of formula (I), uses thereof, processes for the preparation thereof and compositions containing said compounds. These compounds have utility in a variety of therapeutic areas including sexual dysfunction.(I).
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Page/Page column 66
(2009/12/27)
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- MET kinase inhibitors
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The present invention is directed to compounds having the formula I or II: including salts thereof, and methods for using them for the treatment of cancer.
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Page/Page column 25-26
(2008/06/13)
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- Oxalamide derivatives as kinase inhibitors
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The invention is directed to compounds having the following Formula I: and methods of using them for the treatment of proliferative diseases.
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Page/Page column 14
(2008/06/13)
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- Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer
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A new series of androgen receptor targeted agents (ARTA) was prepared and tested in androgen-dependent and -independent prostate cancer cell lines. These agents were bicalutamide analogs with isothiocyanato substituted B-rings. Also, the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure-activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared and tested. The arylisothiocyanato AR ligands showed strong binding affinities to AR ranging from 0.6 to 54 nM. Among them, thioether and ether linkages demonstrated high binding affinities (0.6 and 4.6 nM, respectively) and selective cell growth inhibition (approximately 3- to 6-fold) for LNCaP, an androgen-dependent prostate cancer cell line, when compared to the androgen independent prostate cell lines (DU145, PC-3, and PPC-1) and a bladder cell line (TSU-Pr1). However, the ligands were inactive (IC50>100 mM) in a normal monkey kidney cell line (CV-1) that was used as the control for non-specific toxicity.
- Hwang, Dong Jin,Yang, Jun,Xu, Huiping,Rakov, Igor M.,Mohler, Michael L.,Dalton, James T.,Miller, Duane D.
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p. 6525 - 6538
(2007/10/03)
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- Monocyclic heterocycles as kinase inhibitors
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The present invention is directed to compounds having the formula and methods for using them for the treatment of cancer.
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Page/Page column 35-36
(2008/06/13)
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- ETHER-LINKED HETEROARYL COMPOUNDS
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Compounds of formula (I) are disclosed, as well as methods for synthesizing such compounds and methods of their use. Preferred compounds of formula (I) are potent inhibitors of c-MET/HGFR useful in the treatment of a variety of HGFR-mediated disorders, including cancers.
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Page/Page column 45-46
(2010/02/15)
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- 1,3-Dihydroxybenzene derivatives and colorants containing said compounds
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1,3-Dihydroxybenzene derivatives of general formula (I) or (Ia) or physiologically tolerated, water-soluble thereof wherein R′1 denotes substituted pyridyl group, a pyrimidyl group, a group of formula (IIa) or (IIIa) and the dyeing agents for keratin fibers containing these compounds.
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- Benzoylurea compounds and pesticides containing them
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A benzoylurea compound having the formula: STR1 wherein each of X1 and X2 is a hydrogen atom, a halogen atom or a methyl group, provided that X1 and X2 are not simultaneously hydrogen atoms, Y is independently a
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- Etude des complexes du cobalt (II) transporteurs d'oxygene: Nouvelle synthese du fluoro-3 hydroxy-2 benzaldehyde
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Synthetic chelates of cobalt (II) derived from Schiff bases have remarkable behavior of reversibly absorbing and releasing molecular oxygene.Among these, bis (3-fluorosalicylaldehydeethylenediimide) Co (II) (fluomine: Formula A, X=F) is most interesting in allowing to isolate pure oxygen from air, because it absorbs with extreme rapidity 4.43percent of its weight of oxygen.Fluomine is easily prepared from 3-fluorosalicylaldehyde (3FSA), ethylenediamine and cobalt (II) chloride; but substances such as 3-substituted salicylaldehydes have proven to be extremely difficult to prepare in other than small laboratory quantities from the corresponding ortho-substituted phenol.Many author have prepared 3-fluorosalicylaldehyde, as described in patents, but often these syntheses are very long and the yields are generally less than 20percent.We now describe a new synthesis from o-fluorophenol.Nitration of o-fluorophenol with liquid nitrogen dioxide is convenient: - on the one hand, ortho-substitution to the hydroxyl group, is easy, -on the other hand, the para substituted by-product, is reinserted in the course of the synthesis, so that it is possible to minimize loss of the starting phenol, an expensive product. o-Fluorophenol 1 in solution in pentane, at about 0 deg C, is treated with liquid nitrogen dioxide (slight excess).The reaction is rapid and leads to 2-fluoro 6-nitrophenol 2 which remains in solution, and 2-fluoro 4-nitrophenol 7 which cristallizes rapidly (approximatively 50percent of each one). 2-Fluoro 6-nitrophenol 2 is converted into the anisole 3, the NO2 group of which is catalytically reduced by hydrogen into 3-fluoro 2-methoxy-aminobenzene 4.This amine 4 is diazotized, and treated with formaldoxime to lead to 3-fluoro 2-methoxybenzaldehyde 5 (Eb12 = 82 deg C). 3FSA is finally obtained by heating under reflux anisole 5 and a solution of hydrobromic acid (48percent). 2-Fluoro 4-nitrophenol 7 is converted in five steps into 3-fluoro 2-methoxyaminobenzene 4 by the same reactions as these used for its isomer.Finally the total yield of amine 4 from o-fluorophenol is 73percent, and 3FSA is obtained in 25percent yield.No primary amines are required during the isolation, so that no possible contamination of the final product is possible and therefore the fluomine prepared therefrom is not contaminated and deactivated.
- Aymes, Daniel J.,Paris, Michel R.
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p. 175 - 178
(2007/10/02)
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