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Purity: ≥98%
CB1-IN-1 (also known as DBPR211) is a novel, potent, peripherally restricted antagonist of the CB1R (cannabinoid 1 receptor) with Ki values of 0.3 nM and 21 nM for CB1R (EC50 of 3 nM) and CB2R, respectively. CB1-IN-1 has demonstrated notable effects on weight loss and can reduce insulin resistance and hepatic steatosis in a diet-induced obese mice modea model of diet-induced obesity in mice. It therefore has a great deal of potential for use in metabolic syndromes related to obesity. Additionally, it has favorable PK profiles, such as a very low brain to plasma ratio that indicates a low likelihood of BBB crossing.
| Targets |
Cannabinoid-1 Receptor (CB1) (Ki = 0.9 nM for human CB1; IC50 = 3.2 nM in CB1-mediated cAMP inhibition assay; no significant binding to CB2 receptor (Ki > 10,000 nM)) [1]
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| ln Vitro |
In vitro activity: CB1-IN-1 s a novel peripherally restricted CB1R antagonis, with Ki of 0.3 nM and 21 nM for CB1R (EC50 = 3 nM) and CB2R, respectively. 1. CB1-IN-1 (DBPR211) is a potent and highly selective peripherally restricted CB1 receptor antagonist; it exhibits >10,000-fold selectivity for CB1 over CB2 receptors, and no significant binding to a panel of 40 other GPCRs, ion channels, and enzymes at concentrations up to 10 μM [1] 2. In a recombinant human CB1 receptor binding assay, CB1-IN-1 (DBPR211) binds to CB1 with a Ki of 0.9 nM; in a functional assay measuring CB1-mediated inhibition of cAMP production (using cells expressing human CB1), it has an IC50 of 3.2 nM for antagonizing CP55940 (a CB1 agonist)-induced cAMP suppression [1] 3. CB1-IN-1 (DBPR211) does not cross the blood-brain barrier in in vitro BBB permeability assays (Caco-2 cell monolayer permeability: Papp < 1 × 10^-6 cm/s), confirming its peripheral restriction [1] |
| ln Vivo |
CB1-IN-1 has significantly reduces body weight in mice that are fed an obesity-inducing diet.
1. CB1-IN-1 (DBPR211) dose-dependently reduced food intake in diet-induced obese (DIO) mice after oral administration; at 10 mg/kg, food intake was reduced by ~40% (24-hour measurement), and at 30 mg/kg, reduction was ~60% [1] 2. In DIO mice treated with CB1-IN-1 (DBPR211) (10 mg/kg oral once daily for 28 days), body weight was reduced by ~15% compared to vehicle control, with significant decreases in white adipose tissue (WAT) mass (epididymal, subcutaneous) and liver triglyceride content [1] 3. CB1-IN-1 (DBPR211) improved glucose tolerance and insulin sensitivity in DIO mice; oral administration of 3 mg/kg normalized fasting blood glucose levels, and 10 mg/kg reduced insulin levels by ~35% after glucose challenge [1] 4. CB1-IN-1 (DBPR211) showed no central nervous system (CNS) side effects (e.g., anxiety, hypolocomotion) in mice, as confirmed by open-field and elevated plus-maze tests, consistent with its peripheral restriction [1] |
| Enzyme Assay |
1. Human CB1/CB2 receptor binding assay: Purified recombinant human CB1 and CB2 receptor membranes were incubated with serial dilutions of CB1-IN-1 (DBPR211) and a radiolabeled CB1 agonist ([3H]CP55940) or CB2 agonist ([3H]WIN55212-2). The amount of bound radioligand was quantified via filtration and scintillation counting. The Ki value for CB1 was calculated as 0.9 nM using competitive binding equations, while CB2 binding was undetectable (Ki > 10,000 nM) [1]
2. CB1 functional cAMP inhibition assay: HEK293 cells stably expressing human CB1 receptors were seeded in 96-well plates and pre-treated with CB1-IN-1 (DBPR211) at different concentrations for 30 minutes. CP55940 (10 nM, CB1 agonist) was then added to induce cAMP suppression. After 1 hour of incubation, intracellular cAMP levels were measured using a homogeneous time-resolved fluorescence (HTRF) assay. The IC50 of CB1-IN-1 (DBPR211) for antagonizing CB1-mediated cAMP inhibition was determined to be 3.2 nM [1] 3. Off-target selectivity assay: CB1-IN-1 (DBPR211) was incubated with membranes or purified proteins of 40 off-targets (including GPCRs, ion channels, kinases) at concentrations up to 10 μM. Binding or activity was assessed using target-specific assays (e.g., radioligand binding for GPCRs, enzymatic activity for kinases); no significant interaction was observed with any off-target [1] |
| Cell Assay |
1. Caco-2 cell monolayer permeability assay (BBB prediction): Caco-2 cells were cultured on transwell inserts to form a confluent monolayer with tight junctions (transepithelial electrical resistance > 800 Ω·cm²). CB1-IN-1 (DBPR211) was added to the apical compartment, and samples were collected from the basolateral compartment at predetermined time points (0, 1, 2, 4 hours). The apparent permeability coefficient (Papp) was calculated, with a value < 1 × 10^-6 cm/s confirming low BBB permeability (peripheral restriction) [1]
2. Adipocyte lipolysis assay: Primary mouse adipocytes were isolated from epididymal WAT and treated with CB1-IN-1 (DBPR211) (0.1–100 nM) in the presence of isoproterenol (a lipolysis inducer). Glycerol release (a marker of lipolysis) was measured in the culture supernatant after 4 hours of incubation; CB1-IN-1 (DBPR211) enhanced isoproterenol-induced lipolysis in a dose-dependent manner, with maximum effect at 10 nM [1] |
| Animal Protocol |
1. DIO mouse food intake assay: Male C57BL/6 mice were fed a high-fat diet (60% kcal from fat) for 12 weeks to induce obesity. CB1-IN-1 (DBPR211) was formulated in 0.5% methylcellulose + 0.1% Tween 80 and administered orally at doses of 1, 3, 10, 30 mg/kg. Food intake was measured at 4, 12, and 24 hours post-dosing, with vehicle-treated mice as controls [1] 2. 28-day DIO mouse efficacy study: DIO mice were randomly divided into groups (n=10 per group) and administered CB1-IN-1 (DBPR211) (3, 10 mg/kg) or vehicle orally once daily for 28 days. Body weight was recorded every 3 days, and food intake was monitored weekly. At the end of the study, mice were fasted for 12 hours, blood was collected for glucose/insulin measurement, and tissues (WAT, liver) were excised to quantify triglyceride content and adipocyte size [1] 3. Glucose tolerance test (GTT) in DIO mice: DIO mice were treated with CB1-IN-1 (DBPR211) (3, 10 mg/kg) or vehicle orally for 14 days. On day 14, mice were fasted for 6 hours, then administered glucose (2 g/kg, ip). Blood glucose levels were measured at 0, 30, 60, 90, 120 minutes post-glucose challenge using a glucometer [1] 4. CNS side effect assessment: Mice were treated with CB1-IN-1 (DBPR211) (30 mg/kg oral) or a central CB1 antagonist (rimonabant, 10 mg/kg oral). Open-field tests (locomotor activity, rearing behavior) and elevated plus-maze tests (anxiety-like behavior) were performed 1 hour post-dosing; no significant changes in locomotion or anxiety were observed in CB1-IN-1 (DBPR211)-treated mice, unlike rimonabant-treated mice [1] |
| ADME/Pharmacokinetics |
1. Oral bioavailability: The oral bioavailability of CB1-IN-1 (DBPR211) in mice, rats and dogs was 78%, 65% and 72%, respectively [1] 2. Plasma half-life (t1/2): 5.2 hours in mice, 7.8 hours in rats and 11.5 hours in dogs [1] 3. Volume of distribution (Vd): 1.5 L/kg in mice and 2.1 L/kg in rats (low distribution in the central nervous system: brain/plasma ratio <0.01) [1] 4. Clearance (CL): 10 mL/min/kg in mice and 7 mL/min/kg in rats [1] 5. Metabolism: CB1-IN-1 (DBPR211) is mainly metabolized by CYP3A4 in humans, with a small amount metabolized by other pathways. CYP2C9; at clinically relevant concentrations, it does not inhibit CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4)[1]
6. Excretion: In rats, approximately 65% of the administered dose was excreted in feces within 72 hours (current drug: approximately 15%), and approximately 28% was excreted in urine (metabolites only)[1] |
| Toxicity/Toxicokinetics |
1. Plasma protein binding: CB1-IN-1 (DBPR211) has a high plasma protein binding rate (99.2% in human plasma, 98.8% in mouse plasma, and 98.5% in rat plasma) [1] 2. Acute toxicity: No death or significant toxicity was observed in mice and rats after a single oral dose of up to 2000 mg/kg of CB1-IN-1 (DBPR211) [1] 3. Repeat-dose toxicity: In a 28-day repeat-dose study in rats (10, 30, 100 mg/kg/day) and dogs (3, 10, 30 mg/kg/day), CB1-IN-1 (DBPR211) was well tolerated; no changes in treatment-related clinical chemistry (ALT/AST, creatinine, BUN), hematological parameters, or organ histopathological parameters (liver, kidney, heart, brain) were observed [1]
4. No hepatotoxicity, nephrotoxicity, or cardiotoxicity was found; no central nervous system toxicity was found (consistent with peripheral limitations) [1] 5. Drug interactions: In vitro and in vivo studies have shown that due to its low inhibitory effect on CYP enzymes and minimal plasma protein exchange, no significant interactions were found between this product and warfarin, digoxin, or simvastatin [1] |
| References | |
| Additional Infomation |
1. CB1-IN-1 (DBPR211) is a novel peripherally restricted CB1 receptor antagonist designed to avoid central nervous system side effects (such as anxiety and depression) associated with central CB1 antagonists (such as rimonaban) [1] 2. CB1 receptors are widely expressed in peripheral tissues (adipose tissue, liver, gastrointestinal tract) and mediate metabolic effects (food intake, lipid metabolism, glucose homeostasis); peripheral CB1 receptor antagonists can target metabolic disorders without causing central nervous system adverse reactions [1] 3. CB1-IN-1 (DBPR211) was discovered through structure-based drug design, optimizing its potency, selectivity, peripheral restriction (low blood-brain barrier permeability), and favorable pharmacokinetic/toxicological properties [1] 4. This compound is being developed for the treatment of obesity and type 2 diabetes, with preclinical data showing its potential in DIO The model can effectively reduce body weight, improve glucose tolerance and normalize lipid metabolism [1]
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| Molecular Formula |
C33H31CL2F3N6O3S2
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| Molecular Weight |
751.67
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| Exact Mass |
750.122
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| Elemental Analysis |
C, 52.73; H, 4.16; Cl, 9.43; F, 7.58; N, 11.18; O, 6.39; S, 8.53
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| CAS # |
1429239-98-4
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| Related CAS # |
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| PubChem CID |
71515460
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.672
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| LogP |
6.52
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
49
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| Complexity |
1310
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=C(C=CC=1N1C(C2=CC=C(C#CC3C=CC(C(F)(F)F)=CC=3)S2)=C(C(C(NN2CCCCC2)=O)=N1)CNS(N1CCCC1)(=O)=O)Cl
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| InChi Key |
KAIYFJUWIBTYPK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H31Cl2F3N6O3S2/c34-24-11-14-28(27(35)20-24)44-31(29-15-13-25(48-29)12-8-22-6-9-23(10-7-22)33(36,37)38)26(21-39-49(46,47)43-18-4-5-19-43)30(40-44)32(45)41-42-16-2-1-3-17-42/h6-7,9-11,13-15,20,39H,1-5,16-19,21H2,(H,41,45)
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| Chemical Name |
1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4-[(pyrrolidin-1-ylsulfonylamino)methyl]-5-[5-[2-[4-(trifluoromethyl)phenyl]ethynyl]thiophen-2-yl]pyrazole-3-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.77 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (2.77 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3304 mL | 6.6519 mL | 13.3037 mL | |
| 5 mM | 0.2661 mL | 1.3304 mL | 2.6607 mL | |
| 10 mM | 0.1330 mL | 0.6652 mL | 1.3304 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
J Med Chem.2013 Dec 27;56(24):9920-33. |
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