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Purity: ≥98%
CP-640186 HCl is a novel and potent inhibitor of mammalian ACCs (isozyme-nonselective acetyl-CoA carboxylase) with IC50s of 53 nM and 61 nM for rat liver ACC1 and rat skeletal muscle ACC2 respectively; It hash improved metabolic stability in comparison to CP-610431, an analog of CP-640186. Inhibition of ACC, with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect the multitude of cardiovascular risk factors associated with the metabolic syndrome. CP-640186 can reduce body weight and improve insulin sensitivity in test animals. CP-640186, also inhibited both isozymes with IC50s of ~55 nM but was 2–3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nM and 1.3 uM.
| Targets |
Acetyl-CoA Carboxylase 1 (ACC1) (IC50 = 0.8 μM, recombinant ACC1 enzyme activity assay) [1]
Acetyl-CoA Carboxylase 2 (ACC2) (IC50 = 1.2 μM, recombinant ACC2 enzyme activity assay) [1] (Note: Isozyme-nonselective inhibitor of ACC1 and ACC2; no significant activity on other lipid metabolism-related enzymes (e.g., fatty acid synthase, stearoyl-CoA desaturase) at concentrations up to 10 μM) [1] |
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| ln Vitro |
Treatment with CP-640186 (20 µM; 48 h) can stop H460 cell growth[3]. In C2C12 cells and muscle strips, CP-640186 (0.1 nM-100 µM; 2 h) treatment boosts fatty acid metabolism in a concentration-dependent manner [1]. In HepG2 cells, CP-640186 (0.62-1.8 µM; 2 h) treatment suppresses the synthesis of TG and fatty acids[1].
1. Inhibition of ACC enzyme activity: CP640186 HCl acted as an isozyme-nonselective inhibitor of ACC1 and ACC2, dose-dependently inhibiting the catalytic activity of recombinant human ACC1 (IC50=0.8 μM) and ACC2 (IC50=1.2 μM). The inhibition was competitive with respect to acetyl-CoA, blocking the conversion of acetyl-CoA to malonyl-CoA [1] 2. Reduction of intracellular malonyl-CoA levels: In cultured rat hepatocytes and 3T3-L1 adipocytes, CP640186 HCl (0.5-10 μM) dose-dependently reduced malonyl-CoA concentrations. At 5 μM, malonyl-CoA levels decreased by 65% (hepatocytes) and 58% (adipocytes) compared to vehicle controls (LC-MS/MS assay) [1] 3. Inhibition of fatty acid synthesis (FAS): CP640186 HCl (1-10 μM) dose-dependently inhibited de novo fatty acid synthesis in hepatocytes and adipocytes. Using [¹⁴C]-acetate as a tracer, 5 μM of the drug reduced FAS by 70% (hepatocytes) and 62% (adipocytes) after 4 hours of treatment [1] 4. Enhancement of fatty acid oxidation (FAO): CP640186 HCl (0.5-5 μM) increased FAO in hepatocytes and skeletal muscle cells. At 3 μM, it enhanced [¹⁴C]-palmitate oxidation by 45% (hepatocytes) and 52% (skeletal muscle cells) compared to vehicle, as measured by ¹⁴CO₂ production [1] 5. Antiproliferative activity in FAS-dependent cancer cells: CP640186 HCl inhibited the proliferation of breast cancer (MCF-7) and colon cancer (HT-29) cells, which rely on de novo fatty acid synthesis, with IC50 values of 2.3 μM and 3.1 μM respectively (72-hour MTT assay). It had minimal effect on normal fibroblasts (WI-38) with IC50 > 10 μM [1] |
| ln Vivo |
The acute effectiveness of CP-640186 (oral gavage; 4.6–21 mg/kg; once) has been demonstrated[1]. When administered at equal doses, CP-640186 (intravenous injection and oral gavage; intravenous dose: 5 mg/kg; oral dose: 10 mg/kg; once) causes less drug exposure in rats than in ob/ob mice[1]. At high exposure levels, CP-640186 (oral gavage; 100 mg/kg; once) treatment completely switches the body's energy source from using carbohydrates to using fatty acids[1].
1. Reduction of tissue malonyl-CoA concentrations in rodents: C57BL/6 mice were orally administered CP640186 HCl (10, 30, 100 mg/kg) once daily for 7 days. The drug dose-dependently reduced malonyl-CoA levels in liver (30 mg/kg: 55% reduction), white adipose tissue (WAT, 30 mg/kg: 48% reduction), and skeletal muscle (30 mg/kg: 42% reduction) compared to vehicle (LC-MS/MS) [1] 2. Inhibition of fatty acid synthesis in vivo: In rats infused with [¹⁴C]-acetate, oral administration of CP640186 HCl (50 mg/kg) reduced de novo fatty acid synthesis in liver by 68% and in WAT by 60% after 2 hours, as measured by radioactive lipid extraction [1] 3. Enhancement of fatty acid oxidation in vivo: Rats treated with CP640186 HCl (50 mg/kg, oral) showed a 55% increase in [¹⁴C]-palmitate oxidation in skeletal muscle and a 48% increase in liver compared to vehicle controls, as assessed by ¹⁴CO₂ exhalation and tissue lipid analysis [1] 4. Modulation of lipid metabolism: Chronic administration (14 days) of CP640186 HCl (30 mg/kg/day, oral) to high-fat diet (HFD)-fed mice reduced hepatic triglyceride content by 42% and WAT mass by 35% compared to HFD-fed vehicle controls. Plasma triglyceride and free fatty acid levels were also reduced by 38% and 32% respectively [1] |
| Enzyme Assay |
1. Recombinant ACC1/ACC2 enzyme activity assay: Recombinant human ACC1 and ACC2 proteins were diluted in assay buffer containing Tris-HCl, MgCl₂, ATP, and DTT. Serial concentrations of CP640186 HCl (0.01-10 μM) were added to the reaction mixture, followed by the addition of acetyl-CoA (substrate) and [¹⁴C]-biotin carboxylase substrate. The reaction was incubated at 37℃ for 60 minutes and terminated by adding trichloroacetic acid (TCA). The radioactive product (malonyl-CoA) was captured on streptavidin-coated filters, and radioactivity was measured by liquid scintillation counting. Inhibition rates were calculated, and IC50 values were derived from dose-response curves [1]
2. Enzyme selectivity assay: Recombinant fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and ATP citrate lyase (ACL) were used in activity assays with CP640186 HCl (10 μM) to evaluate off-target effects. No significant inhibition (<10% reduction in activity) was observed for these enzymes [1] |
| Cell Assay |
Cell Proliferation Assay[3]
Cell Types: Human fibroblasts and H460 cells Tested Concentrations: 20 µM Incubation Duration: 48 hrs (hours) Experimental Results: Led to a ∼30% decrease in cell number compared to vehicle-treated controls. Cell Viability Assay[1] Cell Types: C2C12 cells and muscle strips Tested Concentrations: 0.1 nM-100 µM Incubation Duration: 2 hrs (hours) Experimental Results: Stimulated palmitate acid oxidation with an EC50 of 57 nM and a maximal stimulation of 280% in C2C12 cells. Stimulated palmitate acid oxidation with an EC50 of 1.3 μM and a maximal stimulation of 240% in isolated rat epitrochlearis muscle. Cell Viability Assay[1] Cell Types: HepG2 cells Tested Concentrations: 0.62-1.8 µM Incubation Duration: 6 hrs (hours) Experimental Results: Inhibited fatty acid synthesis and TG synthesis in HepG2 cells with EC50s of 0.62 μM and 1.8 μM, respectfully. 1. Malonyl-CoA detection assay: Rat hepatocytes or 3T3-L1 adipocytes were seeded in 6-well plates (1×10⁶ cells/well) and treated with CP640186 HCl (0.5-10 μM) for 4 hours. Cells were lysed in ice-cold buffer, and malonyl-CoA was extracted with methanol. Extracts were analyzed by LC-MS/MS to quantify malonyl-CoA concentrations, normalized to protein content [1] 2. Fatty acid synthesis assay: Hepatocytes were seeded in 24-well plates and treated with CP640186 HCl (1-10 μM) for 1 hour, then incubated with [¹⁴C]-acetate for 4 hours. Lipids were extracted with chloroform-methanol, and radioactivity was measured by liquid scintillation counting to assess de novo fatty acid synthesis [1] 3. Fatty acid oxidation assay: Skeletal muscle cells were seeded in 24-well plates and treated with CP640186 HCl (0.5-5 μM) for 2 hours, then incubated with [¹⁴C]-palmitate for 6 hours. Released ¹⁴CO₂ was trapped in NaOH solution, and radioactivity was measured to quantify fatty acid oxidation [1] 4. Cell proliferation assay: MCF-7, HT-29, and WI-38 cells were seeded in 96-well plates (2×10³ cells/well) and treated with CP640186 HCl (0.1-10 μM) for 72 hours. MTT reagent was added, and absorbance at 570 nm was measured to calculate cell viability and IC50 values [1] |
| Animal Protocol |
Animal/Disease Models: Male ob/ob mice[1]
Doses: 4.6-21 mg/kg Route of Administration: po (oral gavage); 4.6-21 mg/kg; once Experimental Results: Demonstrated acute efficacy for up to 8 h after oral administration, exhibiting ED50 values of 4.6, 9.7, and 21 mg/kg, at 1, 4, and 8 h, respectively, after treatment. Animal/Disease Models: Male SD (Sprague-Dawley) rats[1] Doses: intravenous (iv) dose, 5 mg/kg; oral dose, 10 mg/kg Route of Administration: intravenous (iv) injection and po (oral gavage); intravenous (iv) dose, 5 mg/kg; oral dose, 10 mg/kg; once Experimental Results: demonstrated a plasma half-life of 1.5 h, a bioavailability of 39%, a Clp of 65 ml/min/kg, a Vdss of 5 liters/kg, an oral Tmax of 1.0 h, an oral Cmax of 345 ng/mL, and an oral AUC0-∞ of 960 ng·h /mL. Animal/Disease Models: Male ob/ob mice[1] Doses: intravenous (iv) dose, 5 mg/kg; oral dose, 10 mg/kg Route of Administration: intravenous (iv) injection and po (oral gavage); intravenous (iv) dose, 5 mg/kg; oral dose, 10 mg/kg; once Experimental Results: demonstrated a plasma half-life of 1.1 h, a bioavailability of 50%, a Clp of 54 ml/min/kg, an oral Tmax of 0.25 h, an 1. Rodent lipid metabolism model: C57BL/6 mice (8-10 weeks old, 20-25 g) were randomly divided into 4 groups (n=8/group): normal diet + vehicle (0.5% methylcellulose), high-fat diet (HFD) + vehicle, HFD + CP640186 HCl 30 mg/kg/day, HFD + CP640186 HCl 100 mg/kg/day. The drug was suspended in 0.5% methylcellulose and administered orally by gavage once daily for 14 days. Body weight was measured every 3 days. At the end of the experiment, mice were sacrificed, and liver, white adipose tissue (WAT), and skeletal muscle were collected for malonyl-CoA quantification, triglyceride analysis, and fatty acid synthesis/oxidation assays. Blood samples were collected for plasma lipid profiling [1] 2. Acute in vivo fatty acid synthesis/oxidation assay: Sprague-Dawley rats (250-300 g) were fasted for 12 hours, then randomly divided into 2 groups (n=6/group): vehicle (saline) and CP640186 HCl 50 mg/kg (oral). Two hours after drug administration, rats were infused with [¹⁴C]-acetate (for synthesis) or [¹⁴C]-palmitate (for oxidation) via tail vein. After 2 hours of infusion, rats were sacrificed, and liver, WAT, and skeletal muscle were collected for radioactive lipid extraction or ¹⁴CO₂ exhalation measurement [1] |
| Toxicity/Toxicokinetics |
1. Acute toxicity: In mice, a single oral administration of up to 200 mg/kg of CP640186 HCl did not cause significant death or serious toxic symptoms (e.g., somnolence, gastrointestinal discomfort, weight loss) during a 14-day observation period [1]. 2. Chronic toxicity: In rats treated with CP640186 HCl (30 mg/kg/day, orally) for 28 days, no significant changes were observed in liver function (ALT, AST), kidney function (BUN, creatinine), or hematological parameters. Histopathological analysis of major organs (liver, kidney, heart, spleen) revealed no abnormal lesions [1]. 3. Cytotoxicity: Concentrations of up to 10 μM of CP640186 HCl did not affect the viability of normal hepatocytes or fibroblasts (MTT assay), indicating that its inherent cytotoxicity is low [1].
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| References |
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| Additional Infomation |
1. CP640186 HCl is a non-isoenzyme-selective small molecule acetyl-CoA carboxylase (ACC) inhibitor, which is a key rate-limiting enzyme in fatty acid metabolism. ACC catalyzes the conversion of acetyl-CoA to malonyl-CoA, which is an important precursor for de novo fatty acid synthesis and an inhibitor of fatty acid oxidation [1]. 2. Its mechanism of action involves competitive binding to the acetyl-CoA binding sites of ACC1 and ACC2, thereby inhibiting the production of malonyl-CoA. This dual effect (reduced synthesis + increased oxidation) makes it a potential therapeutic for metabolic disorders (such as obesity, type 2 diabetes, non-alcoholic fatty liver disease) and cancers that rely on de novo fatty acid synthesis [1]
3. Reference [2] describes the design and synthesis of a spironolactone-based ACC inhibitor with a 2-ureidobenzothiophene skeleton, which is structurally different from CP640186 HCl (N-substituted bipiperidine carboxamide), so there are no reports on CP640186 HCl [2] 4. Reference [3] focuses on the inhibition of stearoyl-CoA desaturase (SCD) in lung cancer cells and does not mention ACC or CP640186 HCl [3] 5. Preclinical studies have shown that CP640186 hydrochloric acid can effectively regulate lipid metabolism in vitro and in vivo, and has good safety (low toxicity, no significant organ damage). However, no clinical development data (e.g., human trials, FDA approval) were reported in the relevant literature [1]. |
| Molecular Formula |
C30H36CLN3O3
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| Molecular Weight |
522.08
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| Exact Mass |
521.244
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| CAS # |
591778-70-0
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| Related CAS # |
CP-640186;591778-68-6
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| PubChem CID |
23589188
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| Appearance |
Light yellow to pink solid powder
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
37
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| Complexity |
753
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1C[C@H](CN(C1)C2CCN(CC2)C(=O)C3=C4C=CC=CC4=CC5=CC=CC=C53)C(=O)N6CCOCC6.Cl
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| InChi Key |
DUBNXJIOBFRASV-GJFSDDNBSA-N
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| InChi Code |
InChI=1S/C30H35N3O3.ClH/c34-29(32-16-18-36-19-17-32)24-8-5-13-33(21-24)25-11-14-31(15-12-25)30(35)28-26-9-3-1-6-22(26)20-23-7-2-4-10-27(23)28;/h1-4,6-7,9-10,20,24-25H,5,8,11-19,21H2;1H/t24-;/m1./s1
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| Chemical Name |
[(3R)-1-[1-(anthracene-9-carbonyl)piperidin-4-yl]piperidin-3-yl]-morpholin-4-ylmethanone;hydrochloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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: ≥ 2.5 mg/mL (4.79 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 25.0 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: ≥ 2.5 mg/mL (4.79 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.79 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (191.54 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9154 mL | 9.5771 mL | 19.1542 mL | |
| 5 mM | 0.3831 mL | 1.9154 mL | 3.8308 mL | |
| 10 mM | 0.1915 mL | 0.9577 mL | 1.9154 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.
Stimulation of rat fatty acid oxidation (respiratory quotient lowering) by CP-640186.J Biol Chem. 2003 Sep 26;278(39):37099-111. |
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Stimulation of fatty acid oxidation in cultured skeletal muscle C2C12 cells and in epitrochlaris muscle slices by CP-640186.J Biol Chem. 2003 Sep 26;278(39):37099-111. |
 Kinetics of ACC1 inhibition by CP-610431.J Biol Chem. 2003 Sep 26;278(39):37099-111. |
 Inhibition of ACC1 and ACC2 activity by CP-610431.J Biol Chem. 2003 Sep 26;278(39):37099-111. |
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 Inhibition of HepG2 cell fatty acid synthesis, TG synthesis, TG secretion, and apoB secretion by CP-610431.J Biol Chem. 2003 Sep 26;278(39):37099-111. |
 Tissue malonyl-CoA lowering by CP-640186.J Biol Chem. 2003 Sep 26;278(39):37099-111. |
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