53553-14-3Relevant articles and documents
From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4)
Kl?vekorn, Philip,Pfaffenrot, Bent,Juchum, Michael,Selig, Roland,Albrecht, Wolfgang,Zender, Lars,Laufer, Stefan A.
supporting information, (2020/11/20)
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.
TRANSGLUTAMINASE 2 (TG2) INHIBITORS
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Paragraph 00764, (2020/03/02)
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.
COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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Page/Page column 88-89, (2020/07/06)
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.
Discovery of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists
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
, p. 2229 - 2250 (2018/02/21)
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
PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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Page/Page column 32; 64; 65, (2018/08/12)
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.
Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1receptor antagonist
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
, p. 1556 - 1570 (2017/02/26)
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.
p27 PROTEIN INDUCER
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Paragraph 2881-2885, (2016/10/08)
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.
The second factor as inhibitor XIA pyridonecarboxylic dihydropyridines P1
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Paragraph 0658, (2016/10/08)
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.
AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHα RESPONSES
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Paragraph 00285, (2014/05/24)
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.
5-HT3 RECEPTOR MODULATORS, METHODS OF MAKING, AND USE THEREOF
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Page/Page column 75, (2011/02/24)
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.