910232-84-7
910232-84-7 structure
- Name: CGI-1746
- Chemical Name: 4-tert-butyl-N-[2-methyl-3-[4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxopyrazin-2-yl]phenyl]benzamide
- CAS Number: 910232-84-7
- Molecular Formula: C34H37N5O4
- Molecular Weight: 579.689
- Catalog: Biochemical Inhibitor Angiogenesis BTK inhibitor
- Create Date: 2018-12-15 18:29:42
- Modify Date: 2024-01-02 10:03:11
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CGI-1746 is a potent and highly selective inhibitor of the Btk with IC50 of 1.9 nM.
| Name | 4-tert-butyl-N-[2-methyl-3-[4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxopyrazin-2-yl]phenyl]benzamide |
|---|---|
| Synonyms |
N-[2-Methyl-3-(4-methyl-6-{[4-(4-morpholinylcarbonyl)phenyl]amino}-5-oxo-4,5-dihydro-2-pyrazinyl)phenyl]-4-(2-methyl-2-propanyl)benzamide
4-tert-butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide CGI1746 4-(tert-Butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide CS-0252 Benzamide, N-[3-[4,5-dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(1,1-dimethylethyl)- CGI-1746 N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide |
| Description | CGI-1746 is a potent and highly selective inhibitor of the Btk with IC50 of 1.9 nM. |
|---|---|
| Related Catalog | |
| Target |
IC50: 1.9 nM (Btk) |
| In Vitro | CGI1746 is specific for Btk, with appr 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 has 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[1]. CGI-1746 does not kill cells as well as the irreversible BTK inhibitors at the same drug concentration. CGI-1746 significantly reduces phosphorylation of both the BTK-A and BTK-C proteins, indicating the auto-phosphorylation of the BTK-C isoform is inhibited in a manner similar to BTK-A. CGI-1746 does not kill LNCaP or DU145 prostate cancer cells at the same concentrations as Ibrutinib or AVL-292, but it demonstrates similar inhibition of BTK phosphorylation at tyrosine 233 in the SH3 domain[2]. |
| 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[1]. |
| Cell Assay | 5×103 DU145 cells or 104 LNCaP cells per well, grown on 96 well plates for 24h, are treated with 1 to 30 µM BTK inhibitors. Cells are fixed after 72h with 2.5% formaldehyde, and stained with Hoechst 33342. Control cells are treated with DMSO. Cell images are acquired using an IN Cell Analyzer 2200 high content imaging system, with a 20X objective. At least 9 fields are imaged per single well of each experiment. Cell numbers are determined and statistics performed using IN Cell Investigator 3.4 high content image analysis software. Each experiment is replicated 3 times, and data are presented as mean±SD. Results are considered significant if p < 0.05. |
| References |
| Density | 1.2±0.1 g/cm3 |
|---|---|
| Molecular Formula | C34H37N5O4 |
| Molecular Weight | 579.689 |
| Exact Mass | 579.284546 |
| PSA | 108.79000 |
| LogP | 3.42 |
| Appearance | white solid |
| Index of Refraction | 1.627 |
| Storage condition | -20℃ |