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MedKoo Cat#: 406952 | Name: Firsocostat (ND-630)
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Firsocostat, also known as ND-630, GS-0976 and NDI-010976, is a potent ACC inhibitor. ND-630 interacts 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. 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).

Chemical Structure

Firsocostat (ND-630)
Firsocostat (ND-630)
CAS#1434635-54-7

Theoretical Analysis

MedKoo Cat#: 406952

Name: Firsocostat (ND-630)

CAS#: 1434635-54-7

Chemical Formula: C28H31N3O8S

Exact Mass: 569.1832

Molecular Weight: 569.63

Elemental Analysis: C, 59.04; H, 5.49; N, 7.38; O, 22.47; S, 5.63

Price and Availability

Size Price Availability Quantity
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
200mg USD 1,350.00 Ready to ship
500mg USD 2,650.00 Ready to ship
1g USD 3,850.00 Ready to ship
2g USD 6,250.00 Ready to ship
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Related CAS #
No Data
Synonym
ND-630; ND 630; ND630. NDI-010976; NDI 010976; NDI010976; GS-0976; GS0976; GS 0976; firsocostat;
IUPAC/Chemical Name
(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanoic acid
InChi Key
ZZWWXIBKLBMSCS-FQEVSTJZSA-N
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-/m0/s1
SMILES Code
O=C(O)C(C)(C)N(C(N(C[C@@H](C1=CC=CC=C1OC)OC2CCOCC2)C3=C4C(C)=C(C5=NC=CO5)S3)=O)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
More Info
Biological target:
Firsocostat is an acetyl-CoA carboxylase (ACC) inhibitor; inhibits human ACC1 and ACC2 with IC50 values of 2.1 and 6.1 nM, respectively.
In vitro activity:
To determine if ACC plays a direct role in HSCs (hepatic stellate cells), the human HSC cell line, LX2, was treated with TGF-β1 for 48 h to stimulate procollagen 1 protein production in the presence or absence of FIR (firsocostat) or compound 1. The ALK5 TGF-β receptor inhibitor (RepSox, 10 uM) was used to establish complete inhibition (dotted line, Fig. 1C,D). FIR dose-dependently suppressed procollagen 1 protein levels in LX-2 lysates with a mean EC50 of 5 nM, and complete suppression of procollagen 1 induction was achieved at concentrations above 100 nM (Fig. 1C). Compound 1 had a similar effect on procollagen 1 production in LX2 cells (Fig. S1C). The EC50 of FIR for suppression of DNL in LX-2 HSCs (7 nM) was in good agreement with the EC50 for inhibition of procollagen 1 production (Fig. 1C&E). This finding was extended to a panel of 68 chemically distinct allosteric and catalytic site inhibitors of ACC. As shown in Fig. 1G, there was a strong correlation (R2 = 0.97) between the potency of distinct ACC inhibitors to suppress DNL (de novo lipogenesis) in HepG2 cells and to suppress procollagen 1 production in LX-2 cells, suggesting that inhibition of DNL may be responsible for the block in procollagen production in LX-2 HSCs. Reference: J Hepatol. 2020 Oct; 73(4): 896-905. https://www.journal-of-hepatology.eu/article/S0168-8278(20)30281-6/fulltext
In vivo activity:
Data also showed that GS-0976 at 4 and 16 mg/kg/day robustly lowered hepatic triglyceride content and improved steatosis histologically in WD (Western diet)-fed MC4R (melanocortin 4 receptor) KO mice (Figs 6B and and7). Since GS-0976 at these doses suppressed liver malonyl-CoA content (Fig 10), indicating that it improved hepatic steatosis through the suppression of DNL (de novo lipogenesis) via ACC1/2 inhibition. Another potential reason for the massive reduction of hepatic triglyceride content due to GS-0976 is the enhancement of fatty acid oxidation in the liver by ACC2 inhibition. Suppression of ACC2 with antisense oligonucleotides increased fatty acid oxidation in hepatocytes, and ACC1/2 dual inhibition by the same method further increased fatty acid oxidation compared with inhibition of ACC2 alone. Reference: PLoS One. 2020; 15(1): e0228212. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986730/
Solvent mg/mL mM
Solubility
DMSO 75.0 131.66
DMF 10.0 17.56
Ethanol 3.0 5.27
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 569.63 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. Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, Zagorska A, Hollenback D, Walker K, Liu K, Pendem S, Newstrom D, Brockett R, Mikaelian I, Kusam S, Ramirez R, Lopez D, Li L, Fuchs BC, Breckenridge DG. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol. 2020 Oct;73(4):896-905. doi: 10.1016/j.jhep.2020.04.037. Epub 2020 May 4. PMID: 32376414. 2. Matsumoto M, Yashiro H, Ogino H, Aoyama K, Nambu T, Nakamura S, Nishida M, Wang X, Erion DM, Kaneko M. Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis. PLoS One. 2020 Jan 28;15(1):e0228212. doi: 10.1371/journal.pone.0228212. PMID: 31990961; PMCID: PMC6986730. 3. Lu Y, Su X, Zhao M, Zhang Q, Liu C, Lai Q, Wu S, Fang A, Yang J, Chen X, Yao Y. Comparative RNA-sequencing profiled the differential gene expression of liver in response to acetyl-CoA carboxylase inhibitor GS-0976 in a mouse model of NASH. PeerJ. 2019 Dec 20;7:e8115. doi: 10.7717/peerj.8115. PMID: 31879571; PMCID: PMC6927352.
In vitro protocol:
Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, Zagorska A, Hollenback D, Walker K, Liu K, Pendem S, Newstrom D, Brockett R, Mikaelian I, Kusam S, Ramirez R, Lopez D, Li L, Fuchs BC, Breckenridge DG. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol. 2020 Oct;73(4):896-905. doi: 10.1016/j.jhep.2020.04.037. Epub 2020 May 4. PMID: 32376414.
In vivo protocol:
1. Matsumoto M, Yashiro H, Ogino H, Aoyama K, Nambu T, Nakamura S, Nishida M, Wang X, Erion DM, Kaneko M. Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis. PLoS One. 2020 Jan 28;15(1):e0228212. doi: 10.1371/journal.pone.0228212. PMID: 31990961; PMCID: PMC6986730. 2. Lu Y, Su X, Zhao M, Zhang Q, Liu C, Lai Q, Wu S, Fang A, Yang J, Chen X, Yao Y. Comparative RNA-sequencing profiled the differential gene expression of liver in response to acetyl-CoA carboxylase inhibitor GS-0976 in a mouse model of NASH. PeerJ. 2019 Dec 20;7:e8115. doi: 10.7717/peerj.8115. PMID: 31879571; PMCID: PMC6927352.
1: Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, Huss RS, Zhu Y, Billin AN, Damgaard LH, Buchholtz K, Kjær MS, Balendran C, Myers RP, Loomba R, Noureddin M. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol. 2022 Sep;77(3):607-618. doi: 10.1016/j.jhep.2022.04.003. Epub 2022 Apr 16. PMID: 35439567. 2: Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, Bhandari BR, Gunn N, Caldwell SH, Goodman Z, Wapinski I, Resnick M, Beck AH, Ding D, Jia C, Chuang JC, Huss RS, Chung C, Subramanian GM, Myers RP, Patel K, Borg BB, Ghalib R, Kabler H, Poulos J, Younes Z, Elkhashab M, Hassanein T, Iyer R, Ruane P, Shiffman ML, Strasser S, Wong VW, Alkhouri N; for the ATLAS Investigators. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology. 2021 Feb;73(2):625-643. doi: 10.1002/hep.31622. PMID: 33169409. 3: Alkhouri N, Lawitz E, Noureddin M, DeFronzo R, Shulman GI. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020 Feb;29(2):135-141. doi: 10.1080/13543784.2020.1668374. Epub 2019 Sep 19. PMID: 31519114; PMCID: PMC7063378. 4: Attia SL, Softic S, Mouzaki M. Evolving Role for Pharmacotherapy in NAFLD/NASH. Clin Transl Sci. 2021 Jan;14(1):11-19. doi: 10.1111/cts.12839. Epub 2020 Aug 25. PMID: 32583961; PMCID: PMC7877845. 5: Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, Zagorska A, Hollenback D, Walker K, Liu K, Pendem S, Newstrom D, Brockett R, Mikaelian I, Kusam S, Ramirez R, Lopez D, Li L, Fuchs BC, Breckenridge DG. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol. 2020 Oct;73(4):896-905. doi: 10.1016/j.jhep.2020.04.037. Epub 2020 May 4. PMID: 32376414. 6: Polyzos SA, Katsiki N. Semaglutide, cilofexor, and firsocostat for nonalcoholic steatohepatitis: a dance that may need more than one dancer. Hormones (Athens). 2022 Sep;21(3):513-514. doi: 10.1007/s42000-022-00379-6. Epub 2022 Jun 6. PMID: 35668318. 7: Lawitz EJ, Bhandari BR, Ruane PJ, Kohli A, Harting E, Ding D, Chuang JC, Huss RS, Chung C, Myers RP, Loomba R. Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat. Clin Gastroenterol Hepatol. 2023 Jan;21(1):143-152.e3. doi: 10.1016/j.cgh.2021.12.044. Epub 2022 Jan 6. PMID: 34999207. 8: Weber E, Younis IR, Nelson C, Ding D, Qin A, Xiao D, Watkins TR, Othman AA. Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl- Coenzyme A Carboxylase Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist. J Clin Pharmacol. 2023 May;63(5):560-568. doi: 10.1002/jcph.2206. Epub 2023 Feb 28. PMID: 36700458. 9: Kirby BJ, Lutz JD, Yue MS, Garrison KL, Qin AR, Ampaw L, Beysen C, Myers RP, Kearney BP, Mathias A. Organic Anion Transporting Polypeptide Inhibition Dramatically Increases Plasma Exposure but not Pharmacodynamic Effect nor Inferred Hepatic Intracellular Exposure of Firsocostat. Clin Pharmacol Ther. 2021 May;109(5):1334-1341. doi: 10.1002/cpt.2105. Epub 2020 Nov 25. PMID: 33141923. 10: Dandan M, Han J, Mann S, Kim R, Li K, Mohammed H, Chuang JC, Zhu K, Billin AN, Huss RS, Chung C, Myers RP, Hellerstein M. Acetyl-CoA carboxylase inhibitor increases LDL-apoB production rate in NASH with cirrhosis: prevention by fenofibrate. J Lipid Res. 2023 Mar;64(3):100339. doi: 10.1016/j.jlr.2023.100339. Epub 2023 Feb 2. PMID: 36737040; PMCID: PMC10017426. 11: Chen T, Yao J, Quan K, Xu J, Hang X, Tong Q, Liu G, Luo P, Zeng L, Feng G, Bi H. Repurposing a human acetyl-CoA carboxylase inhibitor firsocostat to treat fungal candidiasis alone and in combination. Antimicrob Agents Chemother. 2023 Nov 29:e0113123. doi: 10.1128/aac.01131-23. Epub ahead of print. PMID: 38018962. 12: Hass DT, Pandey K, Engel A, Horton N, Robbings BM, Lim R, Sadilek M, Zhang Q, Autterson GA, Miller JML, Chao JR, Hurley JB. Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux. bioRxiv [Preprint]. 2023 Nov 8:2023.11.07.566117. doi: 10.1101/2023.11.07.566117. PMID: 37986876; PMCID: PMC10659357. 13: Kovalic AJ, Gozar M, Da BL, Bernstein D, Satapathy SK. Pharmacotherapeutic efficacy on noninvasive fibrosis progression in nonalcoholic fatty liver disease: a systematic review and network meta-analysis. Eur J Gastroenterol Hepatol. 2023 Jan 1;35(1):102-111. doi: 10.1097/MEG.0000000000002463. Epub 2022 Nov 17. PMID: 36468574. 14: Neokosmidis G, Cholongitas E, Tziomalos K. Acetyl-CoA carboxylase inhibitors in non-alcoholic steatohepatitis: Is there a benefit? World J Gastroenterol. 2021 Oct 21;27(39):6522-6526. doi: 10.3748/wjg.v27.i39.6522. PMID: 34754150; PMCID: PMC8554398. 15: Venetsanaki V, Karabouta Z, Polyzos SA. Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis. Eur J Pharmacol. 2019 Nov 15;863:172661. doi: 10.1016/j.ejphar.2019.172661. Epub 2019 Sep 16. PMID: 31536725. 16: Lawitz EJ, Li KW, Nyangau E, Field TJ, Chuang JC, Billin A, Wang L, Wang Y, Huss RS, Chung C, Subramanian GM, Myers RP, Hellerstein MK. Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients. J Lipid Res. 2022 Sep;63(9):100250. doi: 10.1016/j.jlr.2022.100250. Epub 2022 Jul 11. PMID: 35835205; PMCID: PMC9424583. 17: Vijayakumar A, Okesli-Armlovich A, Wang T, Olson I, Seung M, Kusam S, Hollenback D, Mahadevan S, Marchand B, Toteva M, Breckenridge DG, Trevaskis JL, Bates J. Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis. Hepatol Commun. 2022 Sep;6(9):2298-2309. doi: 10.1002/hep4.2011. Epub 2022 Jun 23. PMID: 35735253; PMCID: PMC9426400. 18: Fiorucci S, Biagioli M, Baldoni M, Ricci P, Sepe V, Zampella A, Distrutti E. The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease. Expert Opin Drug Discov. 2021 Oct;16(10):1193-1208. doi: 10.1080/17460441.2021.1916465. Epub 2021 May 5. PMID: 33849361. 19: Kayampilly P, Roeser N, Rajendiran TM, Pennathur S, Afshinnia F. Acetyl Co-A Carboxylase Inhibition Halts Hyperglycemia Induced Upregulation of De Novo Lipogenesis in Podocytes and Proximal Tubular Cells. Metabolites. 2022 Oct 3;12(10):940. doi: 10.3390/metabo12100940. PMID: 36295842; PMCID: PMC9610518. 20: Ströbel S, Kostadinova R, Fiaschetti-Egli K, Rupp J, Bieri M, Pawlowska A, Busler D, Hofstetter T, Sanchez K, Grepper S, Thoma E. A 3D primary human cell- based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates. Sci Rep. 2021 Nov 23;11(1):22765. doi: 10.1038/s41598-021-01951-7. PMID: 34815444; PMCID: PMC8611054.

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