5-(aminomethyl)-1-[(2S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-2,3-dihydro-1H-imidazole-2-thione hydrochloride

• ChemBase编号: 73199
• 分子式: C14H16ClF2N3S
• 平均质量: 331.8117464
• 单一同位素质量: 331.07215265
• SMILES: c1(cc(c2c(c1)C[C@H](CC2)n1c(c[nH]c1=S)CN)F)F.Cl
• Canonical SMILES: NCc1c[nH]c(=S)n1[C@H]1CCc2c(C1)cc(cc2F)F.Cl
• InChI: InChI=1S/C14H15F2N3S.ClH/c15-9-3-8-4-10(1-2-12(8)13(16)5-9)19-11(6-17)7-18-14(19)20;/h3,5,7,10H,1-2,4,6,17H2,(H,18,20);1H/t10-;/m0./s1
• InChIKey: DIPDUAJWNBEVOY-PPHPATTJSA-N

名称和登记号

名称

• IUPAC标准名: 5-(aminomethyl)-1-[(2S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-2,3-dihydro-1H-imidazole-2-thione hydrochloride
• IUPAC传统名: nepicastat hydrochloride
• 别名: SYN117; Nepicastat hydrochloride

登记号

• CAS号: 170151-24-3
• PubChem SID: 162038119
• PubChem CID: 9840545

理论计算性质

• 可自由旋转的化学键: 2
• 里宾斯基五规则: true
• Acid pKa: 10.299601
• 质子受体: 1
• 质子供体: 2
• LogD (pH = 5.5): 0.047576632
• LogD (pH = 7.4): 1.7038869
• Log P: 2.6367137
• 摩尔折射率: 79.6337 cm^3
• 极化性: 29.921957 Å^3
• 极化表面积: 41.29 Å^2

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: Dopamine receptor

产品相关信息

• 成盐信息: HCL

详细说明

Selleck Chemicals - S2695

Research Area

• Description: Cancer

Biological Activity

• Description: Nepicastat hydrochloride is a novel, potent and selective inhibitor of both bovine and human dopamine-β-hydroxylase with IC50 of 8.5 nM and 9 nM, respectively.
• Targets: Bovine dopamine-beta-hydroxylase; Human dopamine-beta-hydroxylase
• IC50: 8.5 nM ^[1]; 9 nM ^[1]
• In Vitro: In vitro, Nepicastat hydrochloride shows the selective and concentration-dependent inhibition effects on bovine and human dopamine-beta-hydroxylase activity with IC50 of 8.5 nM and 9.0 nM, respectively. While Nepicastat hydrochloride has negligible affinity for twelve other enzymes and thirteen neurotransmitter receptors. ^[1]
• In Vivo: In the artery, left ventricle and cerebral cortex of spontaneously hypertensive rats (SHRs), Nepicastat hydrochloride reduces noradrenaline content, and increases dopamine content and dopamine/noradrenaline ratio in a dose-dependent manner. In addition, Nepicastat hydrochloride also produces the similar effects on noradrenaline, dopamine and dopamine/noradrenaline ratio in tissues and plasma of beagle dogs. ^[1] In inactin-anesthetized SHRs, Nepicastat hydrochloride (3 mg/kg, i.v.) produces the antihypertensive effects and causes a significant decrease in renal vascular resistance (38%) and an increase in renal blood flow (22%). ^[2] In dogs with chronic heart failure, low-dose Nepicastat hydrochloride (0.5 mg/kg) prevents left ventricular (LV) dysfunction and remodeling, and combination therapy of Nepicastat hydrochloride and enalapril results in additional improvements in all morphological features. ^[3] In rat brain, Nepicastat hydrochloride at a dose of 50 mg/kg ( i.p.) leads to the reduction of norepinephrine (NE) and blocks cocaine-primed reinstatement of cocaine seeking. ^[4]
• Clinical Trials: Nepicastat hydrochloride is currently in Phase II clinical trials in patients with Posttraumatic Stress Disorder.

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro studies: Bovine and human dopamine-beta-hydroxylase activity are assayed by measuring the conversion of tyramine to octopamine. Human dopamine-beta-hydroxylase is purified from the culture medium of the neuroblastoma cell line SK-N-SH. The assay is performed at pH 5.2 and 32°C in a medium containing 0.125 M sodium acetate, 10 mM fumarate, 0.5 ± 2 μM CuSO₄, 0.1 mg/mL catalase, 0.1 mM tyramine and 4 mM ascorbate. In a typical assay, 0.5 ± 1 mu of enzyme are added to the reaction mixture and, subsequently, a substrate mixture containing catalase, tyramine and ascorbate is added to initiate the reaction (final volume of 0.2 mL). Samples are incubated with or without the appropriate concentration of nepicastat (RS-25560-197, S-enantiomer) or RS-25560-198 (R-enantiomer) at 37 °C for 30-40 minutes. The reaction is quenched by the stop solution containing 25 mM EDTA and 240 μM 3-hydroxytyramine (internal standard). The samples are analysed for octopamine by reverse phase high pressure liquid chromatography (h.p.l.c.) with ultraviolet (u.v.)-detection at 280 nM. The h.p.l.c. run is carried out at a flow rate of 1 mL/min with a LiChroCART 125-4 RP-18 column and isocratic elution with 10 mM acetic acid, 10 mM 1-heptane sulphonic acid, 12 mM tetrabutyl ammonium phosphate and 10% methanol. The remaining % activity is calculated based on controls (without RS 25560), corrected with internal standards and fitted to a non-linear four-parameter concentration-response curve. The activity of nepicastat at twelve selected enzymes and receptors is determined by use of established assays. Binding data are analysed by iterative curve-fitting to a four parameter logistic equation. K_i values are calculated from IC50 values by the Cheng-Pruso? equation. Enzyme inhibitory activity is expressed as IC50 (concentration required to produce 50% inhibition of enzyme activity).
• Protocol: Animal Study ^[1]
• Animal Models: Spontaneously hypertensive rats (SHRs).
• Formulation: Nepicastat hydrochloride is dissolved in distilled water.
• Doses: ≤100 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Stanley WC, et al. Br J Pharmacol. 1997, 121(8), 1803-1809.
• References: [2] Stanley WC, et al. J Cardiovasc Pharmacol. 1998, 31(6), 963-970.
• References: [3] Sabbah HN, et al. Circulation. 2000, 102(16), 1990-1995.
• References: [4] Schroeder JP, et al. Neuropsychopharmacology. 2010, 35(12), 2440-2449.

参考文献

• Stanley WC, et al. Br J Pharmacol. 1997, 121(8), 1803-1809.
• Stanley WC, et al. J Cardiovasc Pharmacol. 1998, 31(6), 963-970.
• Sabbah HN, et al. Circulation. 2000, 102(16), 1990-1995.
• Schroeder JP, et al. Neuropsychopharmacology. 2010, 35(12), 2440-2449.