- From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4)
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The mitogen-activated protein kinase (MAP) kinase 4 (MKK4) was found to be a major regulator of liver regeneration and could be a valuable drug target addressing liver related diseases by restoring its intrinsic regenerative capacity. We report on the synthesis and optimization of novel MKK4 inhibitors following a target-hopping strategy from the FDA-approved BRAFV600E inhibitor PLX4032 (8). Applying an iterative multi-parameter optimization process we carved out essential structural features yielding in compounds with a low nanomolar affinity for MKK4 and excellent selectivity profiles against the main off-targets MKK7 and JNK1, which, upon relevant inhibition, would totally abrogate the pro-regenerative effect of MKK4 inhibition, as well as against the off-targets MAP4K5, ZAK and BRAF with selectivity factors ranging from 40 to 430 for our best-balanced compounds 70 and 73.
- Kl?vekorn, Philip,Pfaffenrot, Bent,Juchum, Michael,Selig, Roland,Albrecht, Wolfgang,Zender, Lars,Laufer, Stefan A.
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supporting information
(2020/11/20)
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- TRANSGLUTAMINASE 2 (TG2) INHIBITORS
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Described herein are compounds and pharmaceutical compositions containing such compounds which inhibit transglutaminase 2 (TG2). Also described herein are methods for using such TG2 inhibitors, alone or in combination with other compounds, for treating diseases or conditions that would benefit from TG2 inhibition.
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Paragraph 00764
(2020/03/02)
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- COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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Herein, compounds, compositions and methods for modulating inclusion formation and stress granules in cells related to the onset of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmological diseases, and viral infections are described.
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Page/Page column 88-89
(2020/07/06)
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- Discovery of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists
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A new class of corticotropin releasing factor 1 (CRF1) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a–e were designed as CRF1 receptor antagonists based on con
- Kojima, Takuto,Mochizuki, Michiyo,Takai, Takafumi,Hoashi, Yasutaka,Morimoto, Sachie,Seto, Masaki,Nakamura, Minoru,Kobayashi, Katsumi,Sako, Yuu,Tanaka, Maiko,Kanzaki, Naoyuki,Kosugi, Yohei,Yano, Takahiko,Aso, Kazuyoshi
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p. 2229 - 2250
(2018/02/21)
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- PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to MKK4 (mitogen-activated protein kinase 4) and their use in promoting liver regeneration or reducing or preventing hepatocyte death. The MKK4 inhibitors selectively inhibit protein kinase MKK4 over protein kinases JNK and MKK7.
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Page/Page column 32; 64; 65
(2018/08/12)
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- Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1receptor antagonist
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Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50= 9.5 nM) and in vitro antagonistic activity (IC50= 88 nM) but is rapidly metabolized by human hepatic microsomes (182 μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure–activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87 μL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50= 4.1 nM), in vitro antagonistic activity (IC50= 44 nM), and slow dissociation from the CRF1receptor. Orally administered compound 24d (6–24 μmol/kg) showed ex vivo CRF1receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1receptor antagonists and the pharmacological profiles of compound 24d.
- Mochizuki, Michiyo,Kojima, Takuto,Kobayashi, Katsumi,Kotani, Etsuo,Ishichi, Yuji,Kanzaki, Naoyuki,Nakagawa, Hideyuki,Okuda, Teruaki,Kosugi, Yohei,Yano, Takahiko,Sako, Yuu,Tanaka, Maiko,Aso, Kazuyoshi
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p. 1556 - 1570
(2017/02/26)
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- p27 PROTEIN INDUCER
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The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G 1 , G 2 , G 3 and G 8 are each independently selected from -N= etc., Ring G 6 is selected from divalent aryl etc., A is selected from amino etc., G 4 is selected from oxygen etc., G 5 is selected from oxygen etc., G 7 is selected from -CH 2 - etc., and R 2 is selected from C 1-6 alkyl etc.
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Paragraph 2881-2885
(2016/10/08)
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- The second factor as inhibitor XIA pyridonecarboxylic dihydropyridines P1
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The present invention provides compounds of Formula (X):(Formula (X), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Paragraph 0658
(2016/10/08)
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- AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHα RESPONSES
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Compounds having the following formula I: or a stereoisomer or pharmaceutically-acceptable salt thereof, where R1, R2, R3, R4, and R5 are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNa, by acting on Tyk-2 to cause signal transduction inhibition.
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Paragraph 00285
(2014/05/24)
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- 5-HT3 RECEPTOR MODULATORS, METHODS OF MAKING, AND USE THEREOF
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Novel 5-HT3 receptor modulators are disclosed. These compounds are used in the treatment of various disorders, including chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, and irritable bowel syndrome. Methods of making these compounds are also described in the present invention.
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Page/Page column 75
(2011/02/24)
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- BENZENE SULFONAMIDE THIAZOLE AND OXAZOLE COMPOUNDS
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 96
(2011/06/16)
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- 2-AMINOBENZIMIDAZOLES FOR TREATING NEURODEGENERATIVE DISEASES
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The invention relates to 2-aminobenzimidazoles useful in treating disorders that are mediated by A2a receptor function, including neurodegenerative diseases including Parkinson's disease and inflammation. The compounds have general formula I:
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Page/Page column 12
(2011/04/18)
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- p27 PROTEIN INDUCER
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The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G1, G2, G3 and G8 are each independently selected from -N= etc., Ring G6 is selected from divalent aryl etc., A is selected from amino etc., G4 is selected from oxygen etc., G5 is selected from oxygen etc., G7 is selected from -CH2- etc., and R2 is selected from C1-6 alkyl etc.
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- BICYCLIC COMPOUND AND PHARMACEUTICAL USE THEREOF
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The present invention provides a compound represented by the formula wherein R1 is a hydrocarbon group optionally having substituent(s), amino optionally having substituent(s), hydroxy optionally having a substituent or a heterocyclic group optionally having substituent(s); R2 is a hydrogen atom or a hydrocarbon group optionally having substituent(s); Xa and Xb are each C, N, O or S; Xc and Xd are each C or N; m is 0-2; n is 1-3; ring A is a 5-membered ring optionally having substituent(s); ring B is a 6-membered ring optionally having substituent(s); and ring C is a 3- to 5-membered ring optionally having substituent(s), provided that when Xa, Xc and Xd are each C, then Xb is N or S, or a salt thereof, which is useful as an agent for the prophylaxis or treatment of a disease relating to an action of melatonin, and the like.
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Page/Page column 109-110
(2010/01/29)
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- Benzene Sulfonamide Thiazole and Oxazole Compounds
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 63
(2009/12/23)
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- THIAZOLE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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The present invention relates to novel Thiazole Derivatives, compositions comprising the Thiazole Derivatives, and methods for using the Thiazole Derivatives for treating or preventing a proliferative disorder, an anti-proliferative disorder, inflammation, arthritis, a central nervous system disorder, a cardiovascular disease, alopecia, a neuronal disease, an ischemic injury, a viral infection, a fungal infection, or a disorder related to the activity of a protein kinase.
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Page/Page column 86
(2009/06/27)
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- TRICYCLIC COMPOUNDS AND USE THEREOF
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There is provided a compound of the formula (I′): wherein x is a nitrogen or CRx, Rx is a hydrogen, etc., R1 is an optionally substituted hydrocarbon group, etc., R2 is an optionally substituted hydrocarbon group, etc., ring A is 5- to 8-membered heterocyclic ring, etc., and each of Y1, Y2 and Y3 is an optionally substituted carbon or a nitrogen, etc.; or a salt thereof or a prodrug thereof, which have CRF receptor antagonistic activity and use thereof.
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Page/Page column 69
(2009/07/25)
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- BENZIMIDAZOLE COMPOUNDS
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There is provided a compound of the formula (1) wherein R1 is an optionally substituted C1-10 alkyl; R2 is H, or a C1-6 alkyl which may be substituted with 1 to 3 substituents; R3 is a 5- or 6-membered aromatic group which may be substituted with 1 to 5 substituents, wherein the 5- or 6-membered aromatic group may be fused with a 5- or 6- membered ring which may be substituted with 1 to 3 C1-6 alkyls; R4 is a hydrogen, a halogen, a hydroxy, a cyano, a C1-6 alkyl or a C1-6 alkoxy; Z is -O-, -S-, -SO-, -SO2-, or - NR5- wherein R5 is a hydrogen or a C1-6 alkyl; or a salt thereof or a prodrug thereof, which have CRF receptor antagonist activity and use thereof.
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Page/Page column 95
(2008/12/05)
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- NOVEL COUMARIN DERIVATIVE HAVING ANTITUMOR ACTIVITY
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The present invention provides a compound represented by general formula (1) below or a pharmaceutically acceptable salt thereof: wherein: X is selected from heteroaryl etc., Y1 and Y2 are selected from -N= etc., Y3 and Y4 are selected from -CH= etc., A is selected from sulfamide etc., R1 is selected from hydrogen etc., and R2 is selected from C1-6 alkyl etc. The compound or salt has sufficiently high antitumor activity, and is useful in the treatment of cell proliferative disorders, particularly cancers. The present invention also provides a pharmaceutical composition containing the compound or salt as an active ingredient.
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Page/Page column 197
(2008/12/04)
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- Palladium-catalyzed indole and azaindole synthesis by direct annulation of electron-poor o-chloroanilines and o-chloroaminopyridines with aldehydes
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A practical process for the synthesis of 2-unsubstituted indoles and azaindoles has been developed by the palladium-catalyzed direct annulation of electron-poor o-chloro/bromoanilines and o-chloroaminopyridines with aldehydes. Coupled with the previous results of Jia and Zhu, this allows rapid access to a variety of 2-unsubstituted indoles and azaindoles starting from simple and easily accessible precursors. Georg Thieme Verlag Stuttgart.
- Xu, Zhengren,Hu, Weimin,Zhang, Fengying,Li, Qingjiang,Lue, Zhiyao,Zhang, Lihe,Jia, Yanxing
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experimental part
p. 3981 - 3987
(2009/05/27)
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- FUSED HETEROCYCLIC COMPOUNDS
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There is provided a CRF receptor antagonist comprising a compound of the formula (I) : wherein R1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano
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-
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- CONDENSED BENZAMIDE COMPOUNDS AND INHIBITORS OF VANILLOID RECEPTOR SUBTYPE 1 (VR1) ACTIVITY
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To provide a compound having an excellent inhibitory effect on vanilloid receptor subtype 1 (VR1) activity which is effective in treating diseases to which the vanilloid receptor subtype 1 (VR1) activity is involved, such as pain, acute pain, chronic pain
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Page/Page column 34
(2010/11/28)
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- Prodrugs of a 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- Combination therapy for the treatment of cancer
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The present invention relates to methods for treatment or prevention of neoplasia disorders using protein tyrosine kinase inhibitors in combination with cyclooxygenase inhibitors, in particular cyclooxygenase-2 selective inhibitors.
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- Pyrrole substituted 2-indolinone protein kinase inhibitors
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-(cycloalkanoheteroarylidenyl)-2-indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkano-heteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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Page column 23
(2010/02/05)
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- Substituted tricyclics
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A class of novel tricyclics is disclosed together with the use of such compounds for inhibiting sPLA2mediated release of fatty acids for treatment of conditions such as septic shock.
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- The chemistry of benzothiadiazole plant activators
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Systemic Acquired Resistance (SAR) is an inducible resistance mechanism in plants that, together with other defence mechanisms, provides broadspectrum and long-lasting disease control. With novel screening techniques the benzo[1,2,3]thiadiazole-7-carboxylic acid derivatives have been identified as a new class of chemicals which stimulate the plant's own defence mechanisms. The synthesis and biological activities of various benzo[1,2,3]thiadiazoles and related structures are described. S-Methyl benzo[1,2,3]thiadiazole-7-carbothioate is the first synthetic chemical 'plant activator' that has been developed for this novel disease control concept.
- Kunz,Schurter,Maetzke
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p. 275 - 282
(2007/10/03)
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- Acylated aminophenylsulfonylureas; preparation and use as herbicides and plant growth regulators
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Acylated aminophenylureas, preparation and use as herbicides and plant growth regulators The compounds of the formula I or their salts STR1 in which G is a radical G1, G2 or G3 STR2 R1 is H or alkyl, R2 is COOH, CSOH or a derivative
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- Process and a composition for immunizing plants against diseases
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A method and composition for the immunization of healthy useful plants against plant diseases containing as active ingredients compounds of formula STR1 in which: X is hydrogen, halogen, hydroxy, methyl, methoxy, HOOC or MOOC; Y is hydrogen, halogen, SO3 H, SO3 M, nitro, hydroxy or amino, M being the molar equivalent of an alkali metal or alkaline earth metal ion that is formed from a corresponding base or basic compound; and Z is cyano or --CO--A; A represents either --OH or --SH, the hydrogen atom of which may also be replaced by the molar equivalent of an inorganic or organic cationic residue, or wherein A represents any other organic residue which has a molecular weight of less than 900 and which may also contain one, or more than one, hetero atom, including the salts of the phytophysiologically tolerable 7-carboxylic acid or 7-thiocarboxylic acid with primary, secondary or tertiary amines or with inorganic bases.
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