Bcl-1 ( IC50 = 1.5 nM )

JD5037 is an inverse agonist with a Ki of 0.35 nM for peripherally restricted (PR) cannabinoid 1 (CB1) receptors. Inverse agonists, or antagonists, of the cannabinoid-1 (CB1) receptor have shown promise as novel treatments for obesity and associated metabolic disorders, including liver disease. Due to the early assumption that therapeutic benefit was primarily based on brain receptor interaction, these agents, representing different chemical series, shared the property of brain penetration. JD5037 exhibits low blood-brain barrier penetration and >700-fold selectivity for CB1 over CB2 as well as >1,000-fold selectivity over a panel of 70 receptors, transporters, and ion channels. Orally bioavailable JD5037 decreases food intake, body weight, and abnormalities related to hormones and metabolism in diet-induced obese mice.

JD5037 (3 mg/kg/day, p.o.) dramatically shrinks tumors and completely eradicates them in mice receiving DEN treatment. In mouse HCC samples, JD5037 reduces the levels of AEA. JD5037 (3 mg/kg/d, i.p.) causes comparable weight losses in obese Magel2-null mice, attenuates the hyperglycemia brought on by the HFD, and lessens the hepatic damage and steatosis brought on by the HFD.

JD-5037 is a new CB1R antagonist with an IC50 of 1.5 nM that is peripherally restricted.

[1]. Peripherally restricted CB1 receptor blockers. Bioorg Med Chem Lett. 2013 Sep 1;23(17):4751-60.

[2]. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome. Mol Metab. 2016 Oct 22;5(12):1187-1199.

[3]. Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms. Hepatology. 2015 May;61(5):1615-26.

Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB 'tone', manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype.[1]

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Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).[2]

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Hepatocellular carcinoma (HCC) has high mortality and no adequate treatment. Endocannabinoids interact with hepatic cannabinoid 1 receptors (CB1Rs) to promote hepatocyte proliferation in liver regeneration by inducing cell cycle proteins involved in mitotic progression, including Forkhead Box M1. Because this protein is highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in murine and human HCC. Postnatal diethylnitrosamine treatment induced HCC within 8 months in wild-type mice but fewer and smaller tumors in CB1R(-/-) mice or in wild-type mice treated with the peripheral CB1R antagonist JD5037, as monitored in vivo by serial magnetic resonance imaging. Genome-wide transcriptome analysis revealed CB1R-dependent, tumor-induced up-regulation of the hepatic expression of CB1R, its endogenous ligand anandamide, and a number of tumor-promoting genes, including the GRB2 interactome as well as Forkhead Box M1 and its downstream target, the tryptophan-catalyzing enzyme indoleamine 2,3-dioxygenase. Increased indoleamine 2,3-dioxygenase activity and consequent induction of immunosuppressive T-regulatory cells in tumor tissue promote immune tolerance.[3]

C27H27CL2N5O3S

572.505

571.121

C, 56.65; H, 4.75; Cl, 12.38; N, 12.23; O, 8.38; S, 5.60

1392116-14-1

1392116-14-1

66553204

White to off-white solid powder

1.4±0.1 g/cm3

731.3±70.0 °C at 760 mmHg

396.1±35.7 °C

0.0±2.4 mmHg at 25°C

1.662

4.58

2

5

9

38

977

2

ClC1C([H])=C([H])C(=C([H])C=1[H])C1[C@@]([H])(C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])N(/C(/N([H])S(C2C([H])=C([H])C(=C([H])C=2[H])Cl)(=O)=O)=N\[C@]([H])(C(N([H])[H])=O)C([H])(C([H])([H])[H])C([H])([H])[H])N=1

GTCSIQFTNPTSLO-RPWUZVMVSA-N

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

(2S)-2-[[[(4S)-5-(4-chlorophenyl)-4-phenyl-3,4-dihydropyrazol-2-yl]-[(4-chlorophenyl)sulfonylamino]methylidene]amino]-3-methylbutanamide

JD-5037; JD 5037; ENZ75DG2Z6; CHEMBL2153670; (2S)-2-[[[(4S)-5-(4-chlorophenyl)-4-phenyl-3,4-dihydropyrazol-2-yl]-[(4-chlorophenyl)sulfonylamino]methylidene]amino]-3-methylbutanamide; (S)-2-((((S)-3-(4-Chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(4-chlorophenylsulfonamido)methylene)amino)-3-methylbutanamide; Butanamide, 2-((((4S)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazol-1-yl)(((4-chlorophenyl)sulfonyl)amino)methylene)amino)-3-methyl-, (2S)-; JD5037

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100~250 mg/mL ( 174.7~436.7 mM）
Water: Insoluble
Ethanol: < 2 mg/mL

Solubility in Formulation 1: ≥ 2.75 mg/mL (4.80 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (4.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)