- From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
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Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
- Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
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p. 1197 - 1219
(2021/02/05)
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- Deuterated acetylene derivatives, its pharmaceutical composition and application
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The invention discloses a deuterated acetylenic derivative, a pharmaceutical composition and application thereof. The deuterated acetylenic derivative comprises one or more of the deuterated acetylenic derivative (I) with curative effective dose, pharmace
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Paragraph 0169; 0171; 0172; 0173
(2018/11/22)
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- A 5, 6, 7, 8-tetrahydro-imidazol [1,2-A] pyrazine synthetic method
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The invention discloses a method for synthesizing 5,6,7,8-tetrahydroimidazole-[1,2-A]-pyrazine. The method comprises the following steps: reacting tetramethypyrazine with chloroacetaldehyde dimethyl to generate indol-[1,2-A]-pyrazine; performing hydrogenation reduction reaction on indol-[1,2-A]-pyrazine in the presence of a palladium-carbon catalyst to generate 5,6,7,8-tetrahydroimidazole-[1,2-A]-pyrazine. The method has the beneficial effects that the raw materials are easily available, the reaction conditions are mild, low-cost chloroacetaldehyde dimethyl and palladium-carbon catalyst are adopted, and the large-scale production is facilitated.
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Paragraph 0028 - 0031
(2016/10/08)
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- BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
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Paragraph 0198
(2015/12/30)
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- Aurora Kinase Modulators and Method of Use
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The present invention relates to chemical compounds having a general formula I wherein A1-8, D′, L1, L2, R1, R6-8 and n are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.
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Paragraph 0532
(2014/11/27)
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- PHTHALAZINONE KETONE DERIVATIVE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL USE THEREOF
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A phthalazinone ketone derivative as represented by formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, a use thereof as a poly (ADP-ribose) polymerase (PARP) inhibitor, and a cancer treatment method thereof.
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Paragraph 0089; 0090
(2013/06/28)
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- PHTHALAZINONE KETONE DERIVATIVE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL USE THEREOF
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A phthalazinone ketone derivative as represented by formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, a use thereof as a poly (ADP-ribose) polymerase (PARP) inhibitor, and a cancer treatment method thereof are described.
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Paragraph 0115; 0116
(2013/06/04)
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- METHODS AND COMPOSITIONS FOR RAF KINASE MEDIATED DISEASES
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The invention discloses methods and compositions for treating or preventing RAF kinase mediated diseases or conditions by administering a compound of Formula 1: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the variables are defined as herein.
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Page/Page column 53
(2013/11/18)
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- 5,6,7,8-TETRAHYDROIMIDAZO[1,2-A]PYRAZINE DERIVATIVES AS P2X7 MODULATORS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein A is hydrogen, C1-4alkyl, C3-6cycloalkyl, C1-3alkoxy, C1-3alkoxy C1-4alkyl, C1-2/s
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Page/Page column 50
(2010/11/17)
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- Substituted Sulfonamide Compounds
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Substituted sulfonamide compounds corresponding to the formula I wherein m, n, p, Q, R1, R2, R3, R4, X, Y and Z have the respective meanings defined herein, pharmaceutical compositions containing such compounds, a process for their preparation, and the use of such compounds for the treatment and/or inhibition of pain and other conditions mediated by bradykinin receptor 1 (B1R) and/or bradykinin receptor 2 (B2R).
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Page/Page column 36
(2009/07/25)
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- SUBSTITUTED SULFONAMIDE DERIVATIVES
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The invention relates to substituted sulfonamide derivatives of the general formula (I'); processes for their preparation, medicaments containing these compounds, and the use of substituted sulfonamide derivatives for the preparation of medicaments
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Page/Page column 106; 107
(2009/08/16)
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- SUBSTITUTED SULFONAMIDE COMPOUNDS
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Substituted sulfonamide derivatives, a process for their preparation, pharmaceutical compositions containing these compounds, and to the use of substituted sulfonamide derivatives in the treatment or inhibition of pain and/or various disorders or disease states.
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Page/Page column 67
(2008/12/06)
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- BICYCLIC HETEROARYL COMPOUNDS
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This invention relates to compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.
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Page/Page column 50
(2008/06/13)
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- Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
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The present invention relates to 8-amino-aryl-substituted imidazopyrazines which modulate the activity of protein kinases (“PKs”). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
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- Imidazo-pyrazine derivatives as ligands for gaba receptors
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A class of imidazo[1,2-α]pyrazine analogues substituted in the 3-position by a substituted phenyl ring, being selective ligands for GABAA receptors which interact more favourably with the α2 and/or α3 subunit than with the α1 subunit, are accordingly of b
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Page/Page column 9
(2008/06/13)
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- Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhbitors
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The present invention relates to 8-amino-aryl-substituted imidazopyrazines which modulate the activity of protein kinases (“PKs”). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
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- 8-alkylaminoimidazo(1,2-a)pyrazines and derivatives, their preparation and their application in therapy
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STR1 Novel 8-alkylamino-imidazo(1,2-a)pyrazines of formula (I) show advantages pharmacological activities. They can be used for medical products in human and veterinary therapy in the field of applications of antispasmodics, uterine relaxants, bronchodila
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- Synthesis of imidazo[1,2-a]pyrazine derivatives with uterine-relaxing, antibronchospastic, and cardiac-stimulating properties
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A series of imidazo[1,2-a]pyrazine derivatives was synthesized by condensation of α-halogenocarbonyl compounds and aminopyrazines. Various compounds resulted from competitive reactions or reagent isomerization and demonstrated in vitro uterine-relaxing and in vivo antibronchospastic activities. On isolated atria, 5-bromoimidazo[1,2-a]pyrazine showed positive chronotropic and inotropic properties; the latter was associated with an increase in the cyclic AMP tissue concentration. Potentiation of the isoproterenol positive inotropic effect of 5-bromoimidazo[1,2-a]pyrazine and the lack of blockade of the 5-bromoimidazo[1,2-a]pyrazine positive inotropic effect by propranolol suggested phosphodiesterase-inhibiting properties.
- Sablayrolles,Cros,Milhavet,Rechenq,Chapat,Boucard,Serrano,McNeill
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p. 206 - 212
(2007/10/02)
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