2-(1-Phenyl-cyclopropylamino)-pyrimidine-5-carboxylic acid hydroxyamide
2-(1-Phenyl-cyclopropylamino)-pyrimidine-5-carboxylic acid hydroxyamide Basic information
- Product Name:
- 2-(1-Phenyl-cyclopropylamino)-pyrimidine-5-carboxylic acid hydroxyamide
- Synonyms:
-
- 2-(1-Phenyl-cyclopropylamino)-pyrimidine-5-carboxylic acid hydroxyamide
- ACY-738
- N-Hydroxy-2-[(1-phenylcyclopropyl)amino]-5-pyrimidinecarboxamide
- ACY 738; ACY738
- 2-(1-phenylcyclopropylamino)-N-hydroxypyrimidine-5-carboxamide
- ACY738;ACY-738;ACY 738
- CS-2244
- 5-Pyrimidinecarboxamide, N-hydroxy-2-[(1-phenylcyclopropyl)amino]-
- CAS:
- 1375465-91-0
- MF:
- C14H14N4O2
- MW:
- 270.29
- Mol File:
- 1375465-91-0.mol
2-(1-Phenyl-cyclopropylamino)-pyrimidine-5-carboxylic acid hydroxyamide Chemical Properties
- Density
- 1.433±0.06 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- DMSO:32.0(Max Conc. mg/mL);118.39(Max Conc. mM)
- form
- A crystalline solid
- pka
- 7.75±0.10(Predicted)
- color
- White to off-white
2-(1-Phenyl-cyclopropylamino)-pyrimidine-5-carboxylic acid hydroxyamide Usage And Synthesis
Description
ACY-738 is an inhibitor of histone deacetylase 6 (HDAC6; IC50 = 1.7 nM). It is selective for HDAC6 over HDAC1-3 (IC50s = 94, 128, and 218 nM, respectively). ACY-738 (5 mg/kg) increases acetylation of α-tubulin in mouse brain. It increases exploratory activity in a novel open-field test and reduces immobility time in a tail suspension test in wild-type, but not neural cell-selective HDAC6 knockout, mice when administered at a dose of 50 mg/kg, indicating anxiolytic and antidepressant-like activity, respectively. ACY-738 (100 mg/kg in the diet) attenuates decreases in caudal nerve sensory nerve action potential (SNAP) amplitude and increases in hind paw mechanical hypersensitivity in a mouse model of peripheral neuropathy induced by vincristine . It decreases hepatorenal cystogenesis in a rat model of polycystic liver disease when administered at a dose of 30 mg/kg.
Uses
ACY-738 is a potent, selective and orally-bioavailable HDAC6 inhibitor, with an IC50 of 1.7 nM; ACY-738 also inhibits HDAC1, HDAC2, and HDAC3, with IC50s of 94, 128, and 218 nM.
in vivo
ACY-738 (5?mg/kg) leads to significant increase in α-tubulin acetylation in whole-brain lysates. ACY-738 (50?mg/kg) fails to produce an enhancement of locomotor activity in WT mice tested in a home cage environment[1]. ACY-738 (5 mg/kg) reaches a maximum plasma concentration of 1310 ng/mL at 0.0830 h following treatment. ACY-738 (5 mg/kg BW) alters BM B cell differentiation, but shows no significant effect on IgG and C3 deposition in NZB/W mice. ACY-738 (20 mg/kg) significantly attenuates the severity of proteinuria in NZB/W F1 mice. ACY-738 (5 mg/kg) shows a significant decrease in anti-dsDNA production in NZB/W mice as they aged. ACY-738 (5, 20 mg/kg) attenuates sera IL-1β production as the NZB/W mice aged. ACY-738 (5 mg/kg) significantly reduces glomerular IL-6 and IL-10 mRNA levels by more than 50% while treatment with 20 mg/kg ACY-738 reduced IL-6 and IL-10 mRNA to non-detectable levels[2].
IC 50
HDAC6: 1.7 nM (IC50); HDAC1: 94 nM (IC50); HDAC2: 128 nM (IC50); HDAC3: 218 nM (IC50)
References
[1] Jochems J, et al. Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology. 2014 Jan;39(2):389-400. DOI:10.1038/npp.2013.207
[2] Regna NL, et al. Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice. Clin Immunol. 2016 Jan;162:58-73. DOI:10.1016/j.clim.2015.11.007
[3] Mithraprabhu S, et al. Histone deacetylase (HDAC) inhibitors as single agents induce multiple myeloma cell death principally through the inhibition of class I HDAC. Br J Haematol. 2013 Aug;162(4):559-62. DOI:10.1111/bjh.12388
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