JD-5006 and JD-5037: Peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities

被引：74
作者：
Chorvat, Robert J. [1 ]
Berbaum, Jennifer [1 ]
Seriacki, Kristine [1 ]
McElroy, John F. [1 ]
机构：
[1] Jenrin Discovery, Wilmington, DE 19810 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 19期
关键词：
CB1 receptor inverse agonist; Metabolic disorders; Diabetes; Liver diseases; Dyslipidemias; Obesity; JD-5006; JD-5037; SLV-319; Peripherally restricted cannabinoid-1 receptor blockers; Rimonabant; CB1; antagonist; BRAIN PENETRATION; CARDIOMETABOLIC RISK; CB2; RECEPTORS; ANTAGONISTS; GLYCOPROTEIN; RIMONABANT; WEIGHT; DRUGS; DISCOVERY; AGONISTS;
D O I：
10.1016/j.bmcl.2012.08.004
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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 CB1 receptors is sufficient to produce many of the beneficial metabolic effects of globally active CB1 blockers. Thus, PR CB1 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. (C) 2012 Elsevier Ltd. All rights reserved.
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收藏
页码：6173 / 6180
页数：8
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