JD5037
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MedKoo CAT#: 530481

CAS#: 1392116-14-1

Description: JD5037 is a peripherally restricted (PR) cannabinoid-1 receptor blocker (CB1R antagonist). 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.


Chemical Structure

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JD5037
CAS# 1392116-14-1

Theoretical Analysis

MedKoo Cat#: 530481
Name: JD5037
CAS#: 1392116-14-1
Chemical Formula: C27H27Cl2N5O3S
Exact Mass: 571.1212
Molecular Weight: 572.505
Elemental Analysis: C, 56.65; H, 4.75; Cl, 12.38; N, 12.23; O, 8.38; S, 5.60

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 650.0 Ready to ship
200.0mg USD 1050.0 Ready to ship
500.0mg USD 1950.0 Ready to ship
1.0g USD 3450.0 Ready to ship
2.0g USD 5850.0 Ready to ship
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Synonym: JD5037; JD-5037; JD 5037.

IUPAC/Chemical Name: (S)-2-(((E)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-chlorophenyl)sulfonamido)methylene)amino)-3-methylbutanamide

InChi Key: GTCSIQFTNPTSLO-RPWUZVMVSA-N

InChi Code: 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

SMILES Code: CC(C)[C@@H](C(N)=O)/N=C(N1N=C(C2=CC=C(Cl)C=C2)[C@@H](C3=CC=CC=C3)C1)/NS(=O)(C4=CC=C(Cl)C=C4)=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: JD-5037 is a potent CB1R antagonist with an IC50 of 1.5 nM.
In vitro activity: Liver samples from both humans and mouse models were investigated. The peripheral CB1 receptor antagonist JD5037, β-arr1 wild type (β-arr1-WT) and β-arr1 knockout (β-arr1-KO) littermate models, and primary hepatic stellate cells (HSCs) were also used. The mechanisms underlying CB1 receptor-regulated HSCs activation in fibrosis and the therapeutic potential of JD5037 were further analysed. CB1 receptors were induced in samples from patients with liver fibrosis and from mouse models. These receptors promoted activation of HSCs in liver fibrosis via recruiting β-arrestin1 and Akt signalling, while blockage of CB1 receptors with JD5037 attenuated CB1 receptor-regulated HSCs activation and liver fibrosis by suppressing β-arrestin1/Akt signalling. Reference: Br J Pharmacol. 2020 Jun;177(12):2830-2847. https://doi.org/10.1111/bph.15010
In vivo activity: JD5037 was administered by oral gavage at 10, 40, and 150 mg/kg/day dose levels for up to 34 days to Sprague Dawley rats, and at 5, 20, and 75 mg/kg/day dose levels for 28 consecutive days to Beagle dogs. In rats, higher incidences of stereotypic behaviors were observed in 10 mg/kg females and 40 mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 and 40 mg/kg during neurobehavioral testing. Sporadic minimal incidences of decreased activity (males) and seizures (both sexes) were observed in rats during daily clinical observations, without any clear dose-relationship. Male dogs at 75 mg/kg during treatment period, but not recovery period, had an increased incidence of gut associated lymphoid tissue hyperplasia and inflammation in the intestine. In both species, highest dose resulted in lower AUCs indicative of non-linear kinetics. Free access to food increased the plasma AUC∞ by ~4.5-fold at 20 mg/kg in dogs, suggesting presence of food may help in systemic absorption of JD5037 in dogs. Based on the study results, 150 mg/kg/day in rats, and 20 and 75 mg/kg/day doses in male and female dogs, respectively, were determined to be the no-observed-adverse-effect-levels (NOAELs). Reference: Regul Toxicol Pharmacol. 2019 Dec;109:104483. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31580887/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 174.67
Ethanol 2.0 3.49

Preparing Stock Solutions

The following data is based on the product molecular weight 572.505 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Tan S, Liu H, Ke B, Jiang J, Wu B. The peripheral CB1 receptor antagonist JD5037 attenuates liver fibrosis via a CB1 receptor/β-arrestin1/Akt pathway. Br J Pharmacol. 2020 Jun;177(12):2830-2847. doi: 10.1111/bph.15010. Epub 2020 Mar 3. PMID: 32017042; PMCID: PMC7236068. 2. Kale VP, Gibbs S, Taylor JA, Zmarowski A, Novak J, Patton K, Sparrow B, Gorospe J, Anand S, Cinar R, Kunos G, Chorvat RJ, Terse PS. Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis. Regul Toxicol Pharmacol. 2019 Dec;109:104483. doi: 10.1016/j.yrtph.2019.104483. Epub 2019 Sep 30. PMID: 31580887; PMCID: PMC7017916.
In vitro protocol: 1. Tan S, Liu H, Ke B, Jiang J, Wu B. The peripheral CB1 receptor antagonist JD5037 attenuates liver fibrosis via a CB1 receptor/β-arrestin1/Akt pathway. Br J Pharmacol. 2020 Jun;177(12):2830-2847. doi: 10.1111/bph.15010. Epub 2020 Mar 3. PMID: 32017042; PMCID: PMC7236068.
In vivo protocol: 1. Kale VP, Gibbs S, Taylor JA, Zmarowski A, Novak J, Patton K, Sparrow B, Gorospe J, Anand S, Cinar R, Kunos G, Chorvat RJ, Terse PS. Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis. Regul Toxicol Pharmacol. 2019 Dec;109:104483. doi: 10.1016/j.yrtph.2019.104483. Epub 2019 Sep 30. PMID: 31580887; PMCID: PMC7017916.

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1: Roger C, Buch C, Muller T, Leemput J, Demizieux L, Passilly-Degrace P, Cinar R, Iyer MR, Kunos G, Vergès B, Degrace P, Jourdan T. Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms. Diabetes. 2020 Oct;69(10):2120-2132. doi: 10.2337/db20-0078. Epub 2020 Jul 17. PMID: 32680936; PMCID: PMC7506827.

2: Tan S, Liu H, Ke B, Jiang J, Wu B. The peripheral CB1 receptor antagonist JD5037 attenuates liver fibrosis via a CB1 receptor/β-arrestin1/Akt pathway. Br J Pharmacol. 2020 Jun;177(12):2830-2847. doi: 10.1111/bph.15010. Epub 2020 Mar 3. PMID: 32017042; PMCID: PMC7236068.

3: Kale VP, Gibbs S, Taylor JA, Zmarowski A, Novak J, Patton K, Sparrow B, Gorospe J, Anand S, Cinar R, Kunos G, Chorvat RJ, Terse PS. Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis. Regul Toxicol Pharmacol. 2019 Dec;109:104483. doi: 10.1016/j.yrtph.2019.104483. Epub 2019 Sep 30. PMID: 31580887; PMCID: PMC7017916.

4: Udi S, Hinden L, Ahmad M, Drori A, Iyer MR, Cinar R, Herman-Edelstein M, Tam J. Dual inhibition of cannabinoid CB1 receptor and inducible NOS attenuates obesity-induced chronic kidney disease. Br J Pharmacol. 2020 Jan;177(1):110-127. doi: 10.1111/bph.14849. Epub 2019 Dec 27. Erratum in: Br J Pharmacol. 2021 Mar;178(5):1250. PMID: 31454063; PMCID: PMC6976880.

5: Godlewski G, Cinar R, Coffey NJ, Liu J, Jourdan T, Mukhopadhyay B, Chedester L, Liu Z, Osei-Hyiaman D, Iyer MR, Park JK, Smith RG, Iwakura H, Kunos G. Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut- Brain Axis. Cell Metab. 2019 Jun 4;29(6):1320-1333.e8. doi: 10.1016/j.cmet.2019.04.012. Epub 2019 May 16. PMID: 31105045; PMCID: PMC6551287.

6: Liu J, Godlewski G, Jourdan T, Liu Z, Cinar R, Xiong K, Kunos G. Cannabinoid-1 Receptor Antagonism Improves Glycemic Control and Increases Energy Expenditure Through Sirtuin-1/Mechanistic Target of Rapamycin Complex 2 and 5'Adenosine Monophosphate-Activated Protein Kinase Signaling. Hepatology. 2019 Apr;69(4):1535-1548. doi: 10.1002/hep.30364. Epub 2019 Mar 6. PMID: 30506571; PMCID: PMC6438767.

7: Liu QR, Huang NS, Qu H, O'Connell JF, Gonzalez-Mariscal I, Santa-Cruz-Calvo S, Doyle ME, Xi ZX, Wang Y, Onaivi ES, Egan JM. Identification of novel mouse and rat CB1R isoforms and in silico modeling of human CB1R for peripheral cannabinoid therapeutics. Acta Pharmacol Sin. 2019 Mar;40(3):387-397. doi: 10.1038/s41401-018-0152-1. Epub 2018 Sep 10. PMID: 30202012; PMCID: PMC6460360.

8: Tam J, Szanda G, Drori A, Liu Z, Cinar R, Kashiwaya Y, Reitman ML, Kunos G. Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling. Mol Metab. 2017 Oct;6(10):1113-1125. doi: 10.1016/j.molmet.2017.06.010. Epub 2017 Jun 24. PMID: 29031713; PMCID: PMC5641628.

9: Hinden L, Udi S, Drori A, Gammal A, Nemirovski A, Hadar R, Baraghithy S, Permyakova A, Geron M, Cohen M, Tsytkin-Kirschenzweig S, Riahi Y, Leibowitz G, Nahmias Y, Priel A, Tam J. Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy. J Am Soc Nephrol. 2018 Feb;29(2):434-448. doi: 10.1681/ASN.2017040371. Epub 2017 Oct 13. PMID: 29030466; PMCID: PMC5791066.

10: Varga B, Kassai F, Szabó G, Kovács P, Fischer J, Gyertyán I. Pharmacological comparison of traditional and non-traditional cannabinoid receptor 1 blockers in rodent models in vivo. Pharmacol Biochem Behav. 2017 Aug;159:24-35. doi: 10.1016/j.pbb.2017.06.012. Epub 2017 Jun 27. PMID: 28666894.

11: Iyer MR, Cinar R, Coffey NJ, Chorvat RJ, Kunos G. Synthesis of S-2-((S)-3-(4 -chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1- carboximidamido)-3-(methyl-d3 )butanamide-d5 , octadeuterated JD5037. J Labelled Comp Radiopharm. 2017 Aug;60(10):460-465. doi: 10.1002/jlcr.3521. Epub 2017 Aug 2. PMID: 28545167; PMCID: PMC5568925.

12: Knani I, Earley BJ, Udi S, Nemirovski A, Hadar R, Gammal A, Cinar R, Hirsch HJ, Pollak Y, Gross I, Eldar-Geva T, Reyes-Capo DP, Han JC, Haqq AM, Gross-Tsur V, Wevrick R, Tam J. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome. Mol Metab. 2016 Oct 22;5(12):1187-1199. doi: 10.1016/j.molmet.2016.10.004. PMID: 27900261; PMCID: PMC5123200.

13: González-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu QR, Cimbro R, Santa- Cruz Calvo S, Ghosh S, Cieśla Ł, Moaddel R, Carlson OD, Witek RP, O'Connell JF, Egan JM. Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism. Sci Rep. 2016 Sep 19;6:33302. doi: 10.1038/srep33302. PMID: 27641999; PMCID: PMC5027555.

14: Mukhopadhyay B, Schuebel K, Mukhopadhyay P, Cinar R, Godlewski G, Xiong K, Mackie K, Lizak M, Yuan Q, Goldman D, Kunos G. Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms. Hepatology. 2015 May;61(5):1615-26. doi: 10.1002/hep.27686. Epub 2015 Feb 17. PMID: 25580584; PMCID: PMC4406817.

15: Jourdan T, Szanda G, Rosenberg AZ, Tam J, Earley BJ, Godlewski G, Cinar R, Liu Z, Liu J, Ju C, Pacher P, Kunos G. Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5420-8. doi: 10.1073/pnas.1419901111. Epub 2014 Nov 24. PMID: 25422468; PMCID: PMC4273328.

16: Chorvat RJ. Peripherally restricted CB1 receptor blockers. Bioorg Med Chem Lett. 2013 Sep 1;23(17):4751-60. doi: 10.1016/j.bmcl.2013.06.066. Epub 2013 Jul 4. PMID: 23902803.

17: Cinar R, Godlewski G, Liu J, Tam J, Jourdan T, Mukhopadhyay B, Harvey-White J, Kunos G. Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology. 2014 Jan;59(1):143-53. doi: 10.1002/hep.26606. Epub 2013 Nov 18. PMID: 23832510; PMCID: PMC3839256.

18: 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. PMID: 22959249.

19: Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, Szanda G, Mukhopadhyay B, Chedester L, Liow JS, Innis RB, Cheng K, Rice KC, Deschamps JR, Chorvat RJ, McElroy JF, Kunos G. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012 Aug 8;16(2):167-79. doi: 10.1016/j.cmet.2012.07.002. Epub 2012 Jul 26. PMID: 22841573; PMCID: PMC3832894.

JD5037

10.0mg / USD 150.0


Additional Information

PR CB(1) inverse agonists may represent a safer alternative to highly brain-penetrant agents for the treatment of metabolic disorders, including diabetes, liver diseases, dyslipidemias, and obesity.