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.
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Chorvat RJ, Berbaum J, Seriacki K, McElroy JF
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.
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6173-80. doi: 10.1016/j.bmcl.2012.08.004. Epub 2012 Aug 20.
- PubMed ID
- 22959249 [ View in PubMed]
- Abstract
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.
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- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Rimonabant Cannabinoid receptor 1 IC 50 (nM) 51 N/A N/A Details