Purine (<i>N</i>)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A<sub>3</sub> Adenosine Receptor Agonists
作者:Dilip K. Tosh、Antonella Ciancetta、Eugene Warnick、Robert O’Connor、Zhoumou Chen、Elizabeth Gizewski、Steven Crane、Zhan-Guo Gao、John A. Auchampach、Daniela Salvemini、Kenneth A. Jacobson
DOI:10.1021/acs.jmedchem.5b01998
日期:2016.4.14
C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki
缺乏环外胺的嘌呤(N)-甲氨基甲酰基5'-N-烷基尿嘧啶核苷A3腺苷受体(A3AR)激动剂是Sonogashira偶联过程中发生意外反应并随后发生氨解的结果。由于初始的C6-Me和C6-苯乙烯基衍生物具有出乎意料的高A3AR亲和力,因此制备了缺少环外胺的其他刚性核苷类似物。其中,C6-Me-(2-苯基乙炔基)和C2-(5-氯噻吩基乙炔基)类似物特别有效,人A3AR Ki值分别为6和42 nM。此外,C2-(5-氯噻吩基)-6-H类似物在A3AR(MRS7220,Ki 60 nM)处具有强效和选择性,并且还可以完全逆转小鼠坐骨神经机械性异常性疼痛(体内3μmol/ kg,口服)。可以通过同源建模和这些超修饰核苷的对接来合理化缺乏C6 H键供体,同时保持A3AR亲和力和功效。该模型表明,稳定特征的适当组合可以部分弥补环外胺的缺乏,而环外胺是在A3AR结合位点识别的其他重要因素。