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Purity: ≥98%
Firsocostat S enantiomer (ND-630 S enantiomer), the S enantiomer of ND-630 (also known as GS-0976; NDI-010976; firsocostat), is a potent inhibitor of ACC (acetyl-CoA carboxylase). As a potent allosteric protein-protein interaction inhibitor, ND-630 interacts within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibits the enzymatic activity of both ACC isozymes, reduces fatty acid synthesis and stimulates fatty acid oxidation in cultured cells and in animals, and exhibits favorable drug-like properties. Chronical administration of ND-630 to rats with diet-induced obesity reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by ND-630 may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.
| Targets |
Human acetyl-CoA carboxylase
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
Measurement of ACC1 and ACC2 Activity and Inhibition.[1]
ACC activity was assessed using a luminescent ADP detection assay (ADP-Glo Kinase Assay Kit) that measures enzymatic activity by quantitating the ADP produced during the enzymatic first half-reaction. Specifically, 4.5 μL of assay buffer containing either recombinant hACC1 (GenBank accession no. NM198834; full length with a C-terminal His-tag, 270 kDa, expressed in Baculovirus-infected Sf9 cell-expression system) or recombinant hACC2 (GenBank accession no. NM001093; full length with C-terminal His-tag, 277 kDa, expressed in a Baculovirus-infected Sf9 cell-expression system) were added to the wells of a 384-well Optiplate followed by 0.5 μL of DMSO or DMSO containing inhibitor. Optiplates were incubated at room temperature for 15 min. Then each well received 5.0 μL of substrate mixture to initiate the reaction. Final assay concentrations were 5 nM hACC1 or hACC2, 20 μM ATP, 10 μM (hACC1 assay) or 20 μM (hACC2 assay) acetyl-CoA, 30 mM (hACC1 assay) or 12 mM (hACC2 assay) NaHCO3, 0.01% Brij35, 2 mM DTT, 5% DMSO, inhibitor in half-log increments between 30 μM and 0.0001 μM. After 60-min incubation at room temperature, 10 μL ADP-Glo Reagent was added to terminate the reaction, and plates were incubated at room temperature for 40 min to deplete remaining ATP. Then Kinase Detection Reagent, 20 μL, was added, and plates were incubated for 40 min at room temperature to convert ADP to ATP. ATP was measured via a luciferin/luciferase reaction using a PerkinElmer EnVision 2104 plate reader to assess luminescence. Soraphen Displacement and Thermal Shift Assays.[1] Displacement of fluorescently labeled Soraphen A (Soraphen-TAMARA) from hACC BC by ND-022 was assessed as previously described. The protein thermal shift assay for measuring protein thermal stability was conducted as previously described, using the environmentally sensitive dye SYPRO Orange with fluorescence data acquired at the end of each 1-min interval using a real-time PCR instrument which increased the temperature from 25 °C to 100 °C in increments of 1 °C/min. |
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| Cell Assay |
Measurement of FASyn and FAOxn in Cultured Cells.[1]
FASyn was evaluated in HepG2 cells by measuring the incorporation of [2-14C]acetate into cellular lipids. FAOxn was assessed in C2C12 cells by measuring the release of [14C]O2 and the formation of [14C]acid-soluble materials from [1-14C]palmitate. |
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| Animal Protocol |
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| References |
Proc Natl Acad Sci U S A.2016 Mar 29;113(13):E1796-805.
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| Additional Infomation |
Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.[1]
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| Molecular Formula |
C28H31N3O8S
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| Molecular Weight |
569.626046419144
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| Exact Mass |
569.18318
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| Elemental Analysis |
C, 59.04; H, 5.49; N, 7.38; O, 22.47; S, 5.63
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| CAS # |
2128714-16-7
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| Related CAS # |
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| PubChem CID |
124672214
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.2
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| SMILES |
CC1=C(SC2=C1C(=O)N(C(=O)N2C[C@H](C3=CC=CC=C3OC)OC4CCOCC4)C(C)(C)C(=O)O)C5=NC=CO5
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| InChi Key |
ZZWWXIBKLBMSCS-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C28H31N3O8S/c1-16-21-24(32)31(28(2,3)26(33)34)27(35)30(25(21)40-22(16)23-29-11-14-38-23)15-20(39-17-9-12-37-13-10-17)18-7-5-6-8-19(18)36-4/h5-8,11,14,17,20H,9-10,12-13,15H2,1-4H3,(H,33,34)/t20-/m1/s1
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| Chemical Name |
2-[1-[(2S)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid
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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) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7555 mL | 8.7776 mL | 17.5553 mL | |
| 5 mM | 0.3511 mL | 1.7555 mL | 3.5111 mL | |
| 10 mM | 0.1756 mL | 0.8778 mL | 1.7555 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.
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