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Abstract：
An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for quantification of CM304, a novel and highly selective sigma-1 receptor antagonist that has recently entered into human clinical trials. A structural analogue of CM304, SN56, was used as the internal standard (IS). Chromatographic separation was achieved on an Acquity UPLC™ BEH C18 (1.7 μm, 2.1 mm × 50 mm) column using a mobile phase [water:methanol (0.1%v/v formic acid; 50:50, %v/v)] at a flow rate of 0.2 mL/min. Mass spectrometric detection was performed in the positive ionization mode with multiple reaction monitoring (MRM) using m/z transitions of 337 > 238 for CM304 and 319 > 220 for the IS. The method was found to be linear and reproducible with a regression coefficient consistently >0.99 for the calibration range of 3 to 3000 ng/mL. The extraction recovery ranged from 91.5 to 98.4% from spiked (7.5, 300 and 2526 ng/mL) plasma quality control samples. The precision (%RSD; 1.1 to 2.9%) and accuracy (%RE; -1.9 to 1.8%) were within acceptable limit. The validated method was successfully applied to a single dose oral and intravenous (I.V.) pharmacokinetic study of CM304 in rats. Following I.V. administration, the compound exhibited adequate exposure along with high extravascular distribution and insignificant amount of extra hepatic metabolism. Copyright © 2016 John Wiley & Sons, Ltd.
摘要：
开发并验证了超高效液相色谱-串联质谱（UPLC-MS/MS）方法，用于定量CM304，这是一种新型且高度选择性的sigma-1受体拮抗剂，最近已进入人体临床试验。CM304的结构类似物SN56用作内标(IS)。色谱分离在AcquityUPLC™BEHC18(1.7μm，2.1mm×50mm）的色谱柱，使用流动相[水：甲醇（0.1％v/v甲酸；50：50，％v/v）]，流速为0.2mL/min。质谱检测在正离子化模式下进行,其中多反应监测(MRM)使用对于CM304为337>238和对于IS为319>220的m/z跃迁。发现该方法在3至3000ng/mL的校准范围内具有线性和可重复性，回归系数始终>0.99。加标（7.5、300和2526ng/mL）血浆质量控制样品的提取回收率为91.5％至98.4％。精密度(%RSD;1.1至2.9%)和准确度(%RE;-1.9至1.8%)在可接受的限度内。经过验证的方法已成功应用于大鼠中CM304的单剂量口服和静脉（I.V.）药代动力学研究。在静脉注射后，该化合物表现出足够的暴露以及高的血管外分布和少量的肝外代谢。版权所有©2016JohnWiley＆Sons，Ltd.
