James Edward, Pertusati Fabrizio, Brancale Andrea, McGuigan Chris
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Bioorg Med Chem Lett. 2017 Mar 15;27(6):1371-1378. doi: 10.1016/j.bmcl.2017.02.011. Epub 2017 Feb 9.
Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents.
先前发表的鞘氨醇-1-磷酸（S1P）受体调节剂苄基醚衍生物已显示出作为治疗神经退行性疾病的可行疗法的潜力，然而，据报道，两种最具S1P选择性的化合物在体内被激酶磷酸化的程度很低。合成了BED化合物（2a、2b）的磷酰胺，目的是生产不依赖激酶的S1P受体调节剂。进行了羧肽酶、人血清和细胞裂解物处理实验。发现前药型BED类似物在酸性和碱性条件下具有可接受的稳定性水平，体外代谢处理实验表明它们可被加工成所需的具有药理活性的单磷酸盐。该研究描述了一个全新治疗剂家族的开发。
