910232-84-7

Basic information

• Product Name: N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide
• Synonyms: N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide;CGI-1746;CGI-1746/CGI1746;N-[3-[4,5-dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxopyrazinyl]-2-methylphenyl]-4-(1,1-dimethylethyl)-benzamide;N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide CGI-1746;4-tert-butyl-N-(2-methyl-3-(4-methyl-6-(4-(morpholine-4-carbonyl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide;GCI1746;N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-met
• CAS NO: 910232-84-7
• Molecular Formula: C₃₄H₃₇N₅O₄
• Molecular Weight: 579.71
• Product Categories: Inhibitors
• Mol File: 910232-84-7.mol
• Article Data: 1

Chemical Properties

• Appearance: /
• Density: 1.22
• Solubility: ≥29 mg/mL in DMSO; insoluble in H2O; ≥6.72 mg/mL in EtOH with gentle warming and ultrasonic
• CAS DataBase Reference: N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide(910232-84-7)
• EPA Substance Registry System: N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide(910232-84-7)

Safety Data

• Hazardous Substances Data: 910232-84-7(Hazardous Substances Data)

Usage

Description

N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide, also known as CGI1746, is a potent and highly selective small-molecule inhibitor of Bruton’s tyrosine kinase (BTK) with an IC50 of 1.9 nM. It is a non-receptor tyrosine kinase that plays a crucial role in B lymphocyte development. CGI1746 blocks both autoand trans-phosphorylation of BTK by occupying an SH3 binding pocket in the un-phosphorylated enzyme. N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide prevents B-cell antigen receptor-mediated B lymphocyte proliferation and suppresses FCγRIII-induced TNFα, IL-1β, and IL-6 production in macrophages. It also reduces cytokine levels within joints and ameliorates symptoms in a mouse model of autoantibody-induced arthritis.

Uses

Used in Pharmaceutical Industry:
CGI1746 is used as a Bruton’s tyrosine kinase (Btk) inhibitor for the development of antitumor drugs. It has the potential to be a promising therapeutic agent for various types of cancer, particularly those involving B-cell lymphocytes. By inhibiting BTK, CGI1746 can help regulate the immune response and reduce inflammation, making it a valuable candidate for the treatment of autoimmune diseases and cancer.
Used in Autoimmune Disease Treatment:
In addition to its antitumor properties, CGI1746 is also used in the treatment of autoimmune diseases. Its ability to suppress cytokine production and reduce inflammation makes it a potential candidate for managing conditions such as rheumatoid arthritis, lupus, and other autoimmune disorders. By targeting BTK, CGI1746 can help alleviate symptoms and improve the quality of life for patients suffering from these diseases.
Used in Research Applications:
CGI1746 is also used in research settings to study the role of BTK in various biological processes. As a potent and selective inhibitor of BTK, it can help researchers gain a better understanding of the kinase's function in immune cell development, signaling pathways, and disease progression. This knowledge can contribute to the development of new therapeutic strategies and drug targets for various diseases, including cancer and autoimmune disorders.

In vitro

CGI1746 is specific for Btk, with ～1,000-fold selectivity over Tec and Src family kinases. In an ATP-free competition binding assay, the dissociation constant for Btk is 1.5 nM. CGI1746 inhibits Btk activity in a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 inhibits both auto-and transphosphorylation steps necessary for enzyme activation. CGI1746 completely inhibits anti-IgM–induced murine and human B cell proliferation, with IC50s of 134 nM and 42 nM, respectively, but had no effect on anti-CD3-and anti-CD28–induced T cell proliferation. CGI1746 potently inhibits the proliferation of CD27+IgG+ B cells isolated from the tonsils of four human donors with an average IC50 of 112 nM. In macrophages, CGI1746 abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. CGI1746 potently inhibits TNFα, IL-1β and, to a lesser extent, IL-6 (three-to eight-fold higher IC50) production in human monocytes stimulated with immobilized or soluble immune complexes.

In vivo

CGI1746 abrogates B cell–dependent arthritis. CGI1746 treatment (100 mg/kg, s.c, twice-daily dosing) results in significant inhibition (97%) of overall clinical arthritis scores. CGI1746 treatment substantially reduces TNFα, IL-1β and IL-6, as well as MCP1 and MIP-1α on both the mRNA and protein level in the passive anti-collagen II antibody–induced arthritis (CAIA) model. CGI1746 shows comparable efficacy to TNFα blockade and significantly reduces clinical scores, as well as joint inflammation, in mice or rats with established arthritis.

Relevant articles and documents

KINASE INHIBITORS, AND METHODS OF USING AND IDENTIFYING KINASE INHIBITORS

Methods of inhibiting BTK activity by inhibiting phosphorylation of Y551 of BTK, methods of treating patients by inhibiting BTK activity by inhibiting phosphorylation of Y551 of BTK, chemical entities that bind to BTK and inhibited complexes are provided.