SR1078性質、用途與生產(chǎn)工藝
SR1078是RORα/γ的激活劑。
| Target | Value |
RORα
()
|
RORγ
()
|
SR1078 is a synthetic RORα/RORγ ligand. SR1078 modulates the conformation of RORγ in a biochemical assay and activates RORα and RORγ driven transcription. Furthermore, SR1078 stimulates expression of endogenous ROR target genes in HepG2 cells that express both RORα and RORγ. In a cell-based chimeric receptor Gal4 DNA-binding domain-NR ligand binding domain cotransfection assay, SR1078 significantly inhibits the constitutive transactivation activity of RORα and RORγ, but has no effect on the activity of FXR, LXRα and LXRβ. In a RORα cotransfection assay, treatment of cells with SR1078 (10 μM) results in a significant increase in transcription. Similarly, in the RORγ cotransfection assay, SR1078 treatment results in a stimulation of RORγ-dependent transcription activity.
SR1078 (2-10 μM; 24 hours) shows a dose-dependent increase in expression of A2BP1, CYP19A1, NLGN1, and IPTR1 in SH-SY5Y cells. EC50’s are in the range of 3-5 μM.
The pharmacokinetic properties of SR1078 are examined in mice and noted significant exposure. Plasma concentrations reach 3.6 μM 1h after a 10 mg/kg i.p. injection of SR1078 and sustained levels of above 800 nM even 8h after the single injection. These levels are sufficient to perform a proof-of-principle experiment to determine if SR1078 treatment would stimulate ROR target gene expression in an animal model. Mice are treated with SR1078 (10 mg/kg; i.p.) and 2h after the injection the livers are harvested and mRNA purified for assessment of
G6Pase
and
FGF21
gene expression.T he expression of both
FGF21
and
G6Pase
is significantly stimulated by SR1078 treatment vs. vehicle control.
SR1078 (10 mg/kg; i.p.) shows a significant 25% reduction in repetitive grooming behavior in the BTBR mice.
生產(chǎn)方法
在氬氣保護下，向含有4-(六氟-2-羥基異丙基)苯胺（1.5M THF溶液，128μL，0.193mmol）的二氯甲烷（275μL）溶液中依次加入N,N-二異丙基乙胺（37μL，0.212mmol）和4-三氟甲基苯甲酰氯（30μL，0.193mmol）。反應混合物在室溫下攪拌8小時后，減壓濃縮。粗產(chǎn)物直接通過硅膠柱色譜法純化，洗脫劑為已烷/乙酸乙酯（8/2），得到59mg（產(chǎn)率71%）的N-[4-[2,2,2-三氟-1-羥基-1-(三氟甲基)乙基]苯基]-4-(三氟甲基)苯甲酰胺（SR1078），為白色粉末。紅外光譜（IR, cm-1）：3404, 3214, 1671, 1602, 1529, 1417, 1322, 1272, 1206, 1190, 1176, 1138, 1117, 1065, 1016, 973, 964, 948, 902, 857, 830, 765, 752, 737, 704, 692。1H NMR（400 MHz, (CD3)2SO）：δ 7.68（d, J = 8.2 Hz, 2H），7.89-7.96（m, 4H），8.16（d, J = 8.2 Hz, 2H），8.66（s, 1H），10.67（s, 1H）。13C NMR（100 MHz, (CD3)2SO）：δ 120.12（2C），125.4（q, J = 4.0 Hz, 2C），125.8, 123.3（2C），128.7（2C），131.5（q, J = 31.9 Hz, 1C），138.4, 140.4, 164.7。質譜（ES-）：m/z = 430（C17H10F9NO2-H+）。熔點：169℃。
參考文獻：
[1] Patent: WO2011/115892, 2011, A1. Location in patent: Page/Page column 5; 87; 88
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6604 - 6609
SR1078
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