898537-77-4

Usage

Uses

Used in Pharmaceutical Industry:
3-TERT-BUTYL-1-(3-METHYLPHENYL)-1H-PYRAZOL-5-AMINE is used as a building block for the synthesis of organic compounds with desired therapeutic properties. Its specific biological activity makes it a valuable component in the development of new pharmaceutical agents, potentially targeting a range of health conditions.
Used in Agrochemical Industry:
In the agrochemical sector, 3-TERT-BUTYL-1-(3-METHYLPHENYL)-1H-PYRAZOL-5-AMINE is utilized as a precursor in the creation of compounds with pesticidal or herbicidal properties. Its integration into these products can enhance their effectiveness in agricultural settings, contributing to crop protection and yield improvement.

Upstream product

• 59997-51-2 trimethylacetylacetonitrile 
• 536-89-0 m-tolylhydrazine 
• 637-04-7 (3-methylphenyl)hydrazine hydrochloride 

Downstream Products

• 1160934-76-8 2,2,2-trichloroethyl (3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)carbamate 
• 1071964-34-5 1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)chroman-8-yl)urea 
• 1071964-66-3 1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-2H-chromen-8-yl)urea 
• 1486470-40-9 N-(3-t-butyl-1-m-tolyl-1H-pyrazol-5-yl)-2-(4-chlorophenyl)-2-oxoacetamide 
• 1486470-39-6 N-(3-t-butyl-1-m-tolyl-1H-pyrazol-5-yl)-2-oxo-2-p-tolylacetamide 
• 1486470-38-5 N-(3-t-butyl-1-m-tolyl-1H-pyrazol-5-yl)-2-oxo-2-phenylacetamide 
• 876299-08-0 1-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-3-(2-{[3-(3-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea 
• 1344738-26-6 1-[2-({3-[2-(benzyloxy)-3-chlorophenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-3-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea 
• 1163730-91-3 1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea 
• 898537-79-6 1-(5-tert-Butyl-2-m-tolyl-2H-pyrazol-3-yl)-3-[4-(6-chloro-pyrimidin-4-yloxy)-3-methoxy-phenyl]-urea 

Relevant academic research and scientific papers

Synthesis and p38 inhibitory activity of some novel substituted N,N′-diarylurea derivatives

We have identified a novel series of substituted N,N′-diarylurea p38α inhibitors. The inhibitory activity of the target compounds against the enzyme p38α, MAPKAPK2 in BHK cells, TNF-α release in LPS-stimulated THP-1 cells and p38α binding experiments were

Biophysical investigation and conformational analysis of p38α kinase inhibitor doramapimod and its analogues

Doramapimod (BIRB 796) is a potent inhibitor of p38α mitogen-activated protein kinase. It contains an aryl-pyrazole scaffold as a pharmacophore critical for binding. The aryl-pyrazole scaffold is not planar and adopts an out-of-plane conformation, which is described by the torsion angle θ. In this letter, we report the chemical synthesis and biophysical characterization of different analogues of doramapimod (3-12) exhibiting distinctly different aryl-pyrazole torsion angle θ values. The torsion angle θ values of the synthesized analogues (3-6) were determined by crystal structural analysis and the binding affinities to p38α kinase investigated by microscale thermophoresis. Our results unveil a clear correlation between kinase binding and the torsion angle θ of tested doramapimod analogues, highlighting the importance of inhibitor conformation for protein binding.

Synthesis and Biological Evaluation of Chromenylurea and Chromanylurea Derivatives as Anti-TNF-a agents that Target the p38 MAPK Pathway

A series of 1-aryl-3-(2H-chromen-5-yl)urea and 1-aryl-3-(chroman-5-yl)urea derivatives were designed, synthesized and evaluated for their inhibitory activities towards TNF-a production in lipopolysaccharide-stimulated THP-1 cells. The most active compound, 40g, inhibited TNF-a release with an IC50 value of 0.033 μM, which is equipotent to that of BIRB796 (IC50 = 0.032 μM).

Synthesis, characterization and antiinflammatory activity of novel pyrazolyl ketoamides

Compounds containing pyrazolylurea group are known to possess potent anti-inflammatory activity by inhibiting cell signalling system. One of the potent compounds has demonstrated CNS related adverse effects in human studies which has further intensified the quest to search potent but safe antiinflammatory agents. In the present study, an attempt has been made to modify the urea group into α-ketoamide group. The synthesis involved the coupling of 5-aminopyrazole with substituted α-keto acids in presence of a coupling agent to afford the desired compounds and the structures of the synthesized compounds have been confirmed by spectral data. Compounds have been screened for antiinflammatory activity by carrageenan induced rat paw method. Compounds 6c, 6e and 6f demonstrate greater than 70% paw oedema protection when compared with indomethacin. The preliminary structure activity relationship suggests that the electron withdrawing groups are essential for potent antiinflammatory activity of compounds.

Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc

The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.

Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors

Kinase disregulation disrupts the intricate network of intracellular signaling pathways and contributes to the onset of diseases such as cancer. Although several kinase inhibitors are on the market, inhibitor selectivity and drug resistance mutations persist as fundamental challenges in the development of effective long-term treatments. Chemical entities binding to less conserved allosteric sites would be expected to offer new opportunities for scaffold development. Because no high-throughput method was previously available, we developed a fluorescence-based kinase binding assay for identifying and characterizing ligands which stabilize the inactive kinase conformation. Here, we present a description of the development and validation of this assay using the serine/threonine kinase p38R. By covalently attaching fluorophores to the activation loop of the kinase, we were able to detect conformational changes and measure the Kd, kon, and koff associated with the binding and dissociation of ligands to the allosteric pocket. We report the SAR of a synthesized focused library of pyrazolourea derivatives, a scaffold known to bind with high affinity to the allosteric pocket of p38R. Additionally, we used protein X-ray crystallography together with our assay to examine the binding and dissociation kinetics to characterize potent quinazoline- and quinoline-based type II inhibitors, which also utilize this binding pocket in p38α. Last, we identified the b-Raf inhibitor sorafenib as a potent low nanomolar inhibitor of p38α and used protein X-ray crystallography to confirm a unique binding mode to the inactive kinase conformation.

DISUBSTITUTED UREAS AS KINASE INHIBITORS

The invention relates to compounds of the formula (I), their use as kinase inhibitors, new pharmaceutical formulations comprising said compounds, said compounds for use in the diagnostic or therapeutic treatment of warm-blooded animals, especially humans,

The design and synthesis of novel α-ketoamide-based p38 MAP kinase inhibitors

We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design which due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME and in vivo PK studies show these compounds to have drug-like characteristics which could result in the development of an oral treatment for inflammatory conditions.

Pyrazole urea-based inhibitors of p38 MAP kinase: From lead compound to clinical candidate

We report on a series of N-pyrazole, N′-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5′-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.