JD5037

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.[1]

JD5037
Identifiers
  • (S)-2-((S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamido)-3-methylbutanamide
ChemSpider
Chemical and physical data
FormulaC27H27Cl2N5O3S
Molar mass572.506 g·mol−1
3D model (JSmol)
  • CC(C)[C@@H](C(=O)N)N/C(=N\S(=O)(=O)C1=CC=C(C=C1)Cl)/N2C[C@@H](C(=N2)C3=CC=C(C=C3)Cl)C4=CC=CC=C4
  • InChI=1S/C27H27Cl2N5O3S/c1-17(2)24(26(30)35)31-27(33-38(36,37)22-14-12-21(29)13-15-22)34-16-23(18-6-4-3-5-7-18)25(32-34)19-8-10-20(28)11-9-19/h3-15,17,23-24H,16H2,1-2H3,(H2,30,35)(H,31,33)/t23-,24+/m1/s1
  • Key:GTCSIQFTNPTSLO-RPWUZVMVSA-N

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.

In a study of mice, JD5037 reduced the consumption of alcohol.[2]

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.[3]

A review on the approaches and compound types being pursued as peripherally restricted CB1 receptor blockers, including JD5037, has been published.[4]

Preclinical Toxicity

A preclinical toxicity study of JD5037 in rats and beagle dogs reported NOAELs in rats (150 mg/kg) and dogs (20 mg/kg in males and 75 mg/kg in females).[5] JD5037 showed non-linear kinetics where high dose levels showed plasma saturation with lower plasma drug concentrations. The plasma concentration (area under the curve, AUC) in dogs that were given free access to food was almost 4.5 times greater compared to the dogs that were fasted prior to dose administration.[5] This indicates that the presence of food in the gastrointestinal tract may increase the absorption of JD5037.

References
  1. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. (August 2012). "Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance". Cell Metabolism. 16 (2): 167–79. doi:10.1016/j.cmet.2012.07.002. PMC 3832894. PMID 22841573.
  2. "Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis". doi:10.1016/j.cmet.2019.04.012. PMC 6551287. PMID 31105045. {{cite journal}}: Cite journal requires |journal= (help)
  3. Chorvat RJ, Berbaum J, Seriacki K, McElroy JF (October 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". Bioorganic & Medicinal Chemistry Letters. 22 (19): 6173–80. doi:10.1016/j.bmcl.2012.08.004. PMID 22959249.
  4. Chorvat RJ (September 2013). "Peripherally restricted CB1 receptor blockers". Bioorganic & Medicinal Chemistry Letters. 23 (17): 4751–60. doi:10.1016/j.bmcl.2013.06.066. PMID 23902803.
  5. Kale, Vijay Pralhad; Gibbs, Seth; Taylor, John A.; Zmarowski, Amy; Novak, Joseph; Patton, Kristin; Sparrow, Barney; Gorospe, Jenni; Anand, Satheesh; Cinar, Resat; Kunos, George (Dec 2019). "Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis". Regulatory Toxicology and Pharmacology. 109: 104483. doi:10.1016/j.yrtph.2019.104483. ISSN 1096-0295. PMC 7017916. PMID 31580887.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.