| Identification | Back Directory | [Name]
RG3039 | [CAS]
1005504-62-0 | [Synonyms]
RG3039
CS-2207
EOS-61154
EOS-62326
PF-6687859
RG-3039; RG3039
RG3039(PF-06687859)
5-[[1-(2,6-Dichlorobenzyl)piperidin-4-yl]methoxy]quinazoline-2,4-diamine
2,4-Quinazolinediamine, 5-[[1-[(2,6-dichlorophenyl)methyl]-4-piperidinyl]methoxy]-
5-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)quinazoline-2,4-diaminedihydrochloride | [Molecular Formula]
C21H23Cl2N5O | [MDL Number]
MFCD28716151 | [MOL File]
1005504-62-0.mol | [Molecular Weight]
432.35 |
| Chemical Properties | Back Directory | [Boiling point ]
648.1±65.0 °C(Predicted) | [density ]
1.375±0.06 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO:2.0(Max Conc. mg/mL);4.6(Max Conc. mM) | [form ]
A solid | [pka]
7.82±0.30(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Uses]
RG3039 (PF-06687859) is an orally bioavailable and brain-penetrant DcpS inhibitor with an IC50 of 0.069 nM. | [Biological Activity]
RG3039 is a brain-penetrant and potent inhibitor against the scavenger mRNA-decapping enzyme DcpS (m7GpppX diphosphatase) in vitro (mouse DcpS IC50 = 3.4 nM) and in mice in vivo (∼90% & ∼80% inhibition of brain DcpSrespectively2 h & 72 h post last 3 mg/kg daily ip. from P1 to P10). In a murine severe spinal muscular atrophy (SMA) modelRG3039 (10-20 mg/kg/d ip. from P1 till death) increases SMAΔ7 mice survival (by 26%) and motor function with a ∼50% increase of VGLUT1 synapses number on L3-L5 motor neurons (33.7/WT mice at P13 vs. 17.2/SMA mice without 26.1/SMA mice with RG3039 treatment). | [in vivo]
RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/ SMA mice), and positively impacts neuromuscular pathologies. In 2B/ SMA mice, RG3039 provides a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention[2]. RG3039 distributes to central nervous system tissues where it robustly inhibits DcpS enzyme activity, but minimally activates SMN expression or the assembly of small nuclear ribonucleoproteins. RG3039 treated SMA mice shows a dose-dependent increase in survival, weight and motor function and it is associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhances survival of conditional SMA mice[3]. | [References]
[1] Gopalsamy A, et al. Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA). J Med Chem. 2017 Apr 13;60(7):3094-3108. DOI:10.1021/acs.jmedchem.7b00124
[2] Gogliotti RG, et al. The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models. Hum Mol Genet. 2013 Oct 15;22(20):4084-101. DOI:10.1093/hmg/ddt258
[3] Van Meerbeke J, et al. The DcpS inhibitor RG3039 improves motor function in SMA mice. Hum Mol Genet. 2013 Oct 15;22(20):4074-83. DOI:10.1093/hmg/ddt257 |
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