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JD5037 is an antiobesity drug candidate which acts as a peripherally-restricted cannabinoid inverse agonist at CB1 receptors. It is very selective for the CB1 subtype, with a Ki of 0.35nM, >700-fold higher affinity than it has for CB2 receptors.
In animal studies, JD5037 does not readily cross the blood brain barrier and thus is not expected to produce the psychiatric side effects in humans which led to the withdrawal of rimonabant from the market. Its antiobesity effects are believed to be mediated by blockade of peripheral CB1 receptors, resulting in decreased leptin expression and secretion and increased leptin clearance by the kidneys. In obese mice given the drug, the resulting resensitization to leptin levels produced decreased food intake, weight loss, and normalized responses to glucose and insulin.
JD5037 is covered in the following US Patents issued to Jenrin Discovery: 8,088,809 (1/3/12) ), 7,666,889 (2/23/10), 7,482,470 (1/27/09). The synthesis of JD-5037 and related analogs along with structure activity relationships has been reported.
A review on the approaches and compound types being pursued as peripherally restricted CB1 receptor blockers, including JD5037, has been published.
- Tam, J.; Cinar, R.; Liu, J.; Godlewski, G.; Wesley, D.; Jourdan, T.; Szanda, G.; Mukhopadhyay, B.; Chedester, L.; Liow, J. S.; Innis, R. B.; Cheng, K.; Rice, K. C.; Deschamps, J. R.; Chorvat, R. J.; McElroy, J. F.; Kunos, G. (2012). "Peripheral Cannabinoid-1 Receptor Inverse Agonism Reduces Obesity by Reversing Leptin Resistance". Cell Metabolism. 16 (2): 167–179. PMC . PMID 22841573. doi:10.1016/j.cmet.2012.07.002.
- Chorvat, Robert J.; Berbaum, Jennifer; Seriacki, Kristine; McElroy, John F. (2012). "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. 22 (19): 6173–6180. doi:10.1016/j.bmcl.2012.08.004.
- Chorvat, Robert J. (2013). "Peripherally restricted CB-1 receptor blockers". Bioorg. Med. Chem. Lett. 23 (17): 4751–4760. doi:10.1016/j.bmcl.2013.06.066.