| Identification | Back Directory | [Name]
CEP 33779 | [CAS]
1257704-57-6 | [Synonyms]
CS-1066
CEP 33779 USP/EP/BP
CEP33779; CEP-33779; CEP 33779.
N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridi
N-[3-(4-methylpiperazin-1-yl)phenyl]-8-(4-methylsulfonylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
[8-(4-Methylsulfonylphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl][3-(4-methylpiperazin-1-yl)phenyl]amine
N-[3-(4-Methyl-1-piperazinyl)phenyl]-8-[4-(methylsulfonyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-amine
[1,2,4]Triazolo[1,5-a]pyridin-2-amine, N-[3-(4-methyl-1-piperazinyl)phenyl]-8-[4-(methylsulfonyl)phenyl]-
{[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]-pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine} | [Molecular Formula]
C24H26N6O2S | [MDL Number]
MFCD22683932 | [MOL File]
1257704-57-6.mol | [Molecular Weight]
462.57 |
| Chemical Properties | Back Directory | [density ]
1.35 | [storage temp. ]
Store at -20°C | [solubility ]
≥23.15 mg/mL in DMSO with gentle warming; insoluble in EtOH | [form ]
solid | [pka]
7.78±0.42(Predicted) | [color ]
Light yellow to yellow |
| Hazard Information | Back Directory | [Description]
Janus kinases (JAKs) are non-receptor kinases that mediate signaling through cytokine receptors, often to members of the signal transducer and activator of transcription family. CEP-33779 is a potent, orally available inhibitor of JAK2 (IC50 = 1.3 nM). It shows 65-fold selectivity for JAK2 over JAK3. In mouse models of systemic lupus erythematosus, CEP-33779 reduces the production of inflammatory cytokines, decreases splenomegaly and lymphomegaly, and extends survival. It also diminishes inflammatory signaling and improves clinical scores in mice during collagen antibody-induced arthritis and collagen type II-induced arthritis. CEP-33779 induces regression of established colorectal tumors in mice, reducing angiogenesis and proliferation of tumor cells. | [Uses]
CEP-33779 acts as an orally available inhibitor of JAK2 reducing the production of inflammatory cytokines and decreasing splenomegaly. Anti-arthritic agent. Anticancer agent. | [Synthesis]
GENERAL STEPS: To an oven-dried reaction tube was added palladium acetate (10 mg), 2,2'-bis(dicyclohexylphosphino)biphenyl (30 mg), 8-[4-(methylsulfonyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-amine (75 mg), 1-(3-bromophenyl)-4-methylpiperazine (80 mg), cesium carbonate (270 mg) and 1 ,4-dioxane (5 mL). The reaction tube was evacuated and backflushed three times with nitrogen and then sealed. The reaction mixture was heated at 80°C for 72 hours. After completion of the reaction, the mixture was cooled to room temperature. The cooled mixture was diluted with dichloromethane (10 mL), filtered through a diatomaceous earth plug and rinsed with dichloromethane. The filtrate was concentrated by evaporation and purified by column chromatography (using an ISCO automated purification system, an amine-modified silica gel column, and an eluent of 5% to 100% ethyl acetate in hexane solution). The target compound N-[3-(4-methyl-1-piperazinyl)phenyl]-8-[4-(methylsulfonyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Compound A) was obtained as a yellow solid (70 mg). Melting point: 232-234 °C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 7.5 Hz, 2H), 8.08 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.27- 7.20 (m, 1H), 7.04-6.95 (m, 2H), 6.84 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H). MS: MS = 463 (MH)+. | [in vivo]
CEP-33779 exhibits a favorable PK profile in nude mice, an iv half-life of 1 h, moderate distribution (Vd=2.6 L/kg), and measurable oral exposure with an estimated bioavailability of 33%. It demonstrates antitumor efficacy in the CWR22 xenograft model; oral dosing for 14 days at 30 mg/kg bid results in tumor stasis and partial regressions in 5/10 animals[1]. CEP-33779 administration results in an almost complete shrinkage of tumors in most animals; few remaining tumor nodules were small, poorly vascularized, and had a necrotic appearance. CEP-33779 suppressed activation of NF-κB in tumors[2]. | [target]
JAK2 | [IC 50]
JAK2: 1.8 nM (IC50); JAK3: 150 nM (IC50) | [References]
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5243 - 5254
[2] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
[3] Patent: EP2648728, 2016, B1. Location in patent: Paragraph 0047 |
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