Jenrin Discovery, 2515 Lori Lane North, Wilmington, DE 19810, USA.
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6173-80. doi: 10.1016/j.bmcl.2012.08.004. Epub 2012 Aug 20.
Analogs of SLV-319 (Ibipinibant), a CB1 receptor inverse agonist, were synthesized with functionality intended to limit brain exposure while maintaining the receptor affinity and selectivity of the parent compound. Structure activity relationships of this series, and pharmacology of two lead compounds, 16 (JD-5006) and 23 (JD-5037) showing little brain presence as indicated by tissue distribution and receptor occupancy studies, are described. Effects with one of these compounds on plasma triglyceride levels, liver weight and enzymes, glucose tolerance and insulin sensitivity support the approach that blockade of peripheral CB(1) receptors is sufficient to produce many of the beneficial metabolic effects of globally active CB(1) blockers. Thus, PR CB(1) inverse agonists may indeed represent a safer alternative to highly brain-penetrant agents for the treatment of metabolic disorders, including diabetes, liver diseases, dyslipidemias, and obesity.
SLV-319（Ibipinibant）的类似物是一种 CB1 受体反向激动剂，其合成具有限制脑暴露的功能，同时保持母体化合物的受体亲和力和选择性。该系列的构效关系以及两种先导化合物 16（JD-5006）和 23（JD-5037）的药理学研究，这些化合物的脑内存在较少，如组织分布和受体占有率研究所示，都有描述。其中一种化合物对血浆甘油三酯水平、肝脏重量和酶、葡萄糖耐量和胰岛素敏感性的影响支持这样一种观点，即阻断外周 CB1 受体足以产生全球活性 CB1 阻滞剂的许多有益代谢作用。因此，PR CB1 反向激动剂确实可能是治疗代谢紊乱（包括糖尿病、肝脏疾病、血脂异常和肥胖症）的高度脑穿透性药物的更安全替代品。
