| Identification | Back Directory | [Name]
N-(2-(2-(2-Methoxy-4-MorpholinophenylaMino)-5-fluoropyriMidin-4-ylaMino)phenyl)MethanesulfonaMide | [CAS]
1191911-26-8 | [Synonyms]
CZC-25146
CHEMBL2397014
LRRK2 Inhibitor II
LRRK2 INHIBITOR II;CZC25146;CZC 25146
N-(2-(2-(2-Methoxy-4-MorpholinophenylaMino)-5-fluoropyriMidin-4-ylaMino)phenyl)MethanesulfonaMide
N-(2-((5-fluoro-2-((2-methoxy-4-
morpholinophenyl)amino)pyrimidin-
4-
yl)amino)phenyl)methanesulfonamide
N-[2-[[5-Fluoro-2-[[2-methoxy-4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]amino]phenyl]methanesulfonamide
CZC-25146/N-(2-(2-(2-Methoxy-4-MorpholinophenylaMino)-5-fluoropyriMidin-4-ylaMino)phenyl)MethanesulfonaMide
Methanesulfonamide, N-[2-[[5-fluoro-2-[[2-methoxy-4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]amino]phenyl]- | [Molecular Formula]
C22H25FN6O4S | [MDL Number]
MFCD28160475 | [MOL File]
1191911-26-8.mol | [Molecular Weight]
488.54 |
| Chemical Properties | Back Directory | [Boiling point ]
697.4±65.0 °C(Predicted) | [density ]
1.436±0.06 g/cm3(Predicted) | [storage temp. ]
Inert atmosphere,2-8°C | [solubility ]
≥24.45 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O | [form ]
solid | [pka]
8.48±0.10(Predicted) | [color ]
Pale purple to purple |
| Hazard Information | Back Directory | [Description]
CZC-25146 is a potent inhibitor of leucine-rich repeat kinase 2 (LRRK2; IC50 = 4.76 nM for the human recombinant kinase). It also inhibits LRRK2G2019S, a mutant linked to neurotoxicity and Parkinson’s disease, with an IC50 value of 6.87 nM. CZC-25146 is selective for LRRK2 over a panel of kinases in HeLa cell lysates, Jurkat/Ramos mixed cell lysates, as well as whole mouse brain extracts (IC50s = >2 μM). It reduces LRRK2G2019S-induced cell injury in rat primary cortical neurons. | [Uses]
CZC-25146 is a compound that acts as an inhibitor of LRRK2, a factor in the expression of Parkinsons’s disease, and is ATP-competitive. | [in vivo]
CZC-25146 (250 mg/kg; p.o.; 14 days) reduces the ATZ polymer levels in over expressing human polymeric ATZ mice[3].
CZC-25146 (1 mg/kg for i.v.; 5 mg/kg for p.o.; single dosage) exhibits relatively good pharmacokinetic properties and an extensive distribution throughout animal body following intravenous injection into mice[1]. | Animal Model: | Genetically modified male mice (6 weeks; over expressing human polymeric ATZ)[3] | | Dosage: | 250 mg/kg | | Administration: | p.o.; 14 days | | Result: | Dramatically and reproducibly reduced the ATZ polymer levels with an overall reduction from 60% in the control group to 37%. |
| Animal Model: | Male CD-1 mice[1] | | Dosage: | 1 mg/kg for i.v.; 5 mg/kg for p.o. | | Administration: | i.v. and p.o.; single dosage | | Result: | Pharmacokinetic Parameters of CZC-25146 in male CD-1 mice[1].
| i.v. (1 mg/kg) | p.o. (5 mg/kg) | | CL (L/h/kg) | 2.3 | | | Vss (L/kg) | 5.4 | | | t1/2 (h) | 1.6 | 1 | | tmax (h) | 0 | 0.25 | | Cmax (ng/mL) | 154 | 1357 | | AUClast (ng/mL·h) | 419 | 2878 | | AUCinf (ng/mL·h) | 434 | 2894 | | F (%) | | 133 |
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| [storage]
Store at -20°C | [References]
[1] ramsden n, perrin j, ren z, et al. chemoproteomics-based design of potent lrrk2-selective lead compounds that attenuate parkinson’s disease-related toxicity in human neurons. acs chemical biology, 2011, 6(10): 1021-1028.
[2] troxler t, greenidge p, zimmermann k, et al. discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of lrrk2. bioorganic & medicinal chemistry letters, 2013, 23(14): 4085-4090. |
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