firsocostat   Click here for help

GtoPdb Ligand ID: 10645

Synonyms: GS-0976 | GS-ACC | ND-630 | NDI-010976
Compound class: Synthetic organic
Comment: Firsocostat (GS-0976) is a liver-directed acetyl-CoA carboxylase (ACC) inhibitor [2]. It was initially identified by Nimbus Therapeutics [3], and is being developed by Gilead as an antilipemic agent for potential to treat non-alcoholic steatohepatitis (NASH) [1]. Firsocostat is an allosteric inhibitor that binds to the ACC biotin carboxylase dimerization site, rather than to the previously targeted carboxyltransferase domain. The firsocostat-ACC interaction mimics the physiological inhibition of ACC by AMPK.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 1
Rotatable bonds 9
Topological polar surface area 163.26
Molecular weight 569.18
XLogP 3.12
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES COc1ccccc1[C@H](Cn1c(=O)n(c(=O)c2c1sc(c2C)c1ncco1)C(C(=O)O)(C)C)OC1CCOCC1
Isomeric SMILES COc1ccccc1[C@H](Cn1c(=O)n(c(=O)c2c1sc(c2C)c1ncco1)C(C(=O)O)(C)C)OC1CCOCC1
InChI 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
InChI Key ZZWWXIBKLBMSCS-FQEVSTJZSA-N
References
1. Alkhouri N. (2020)
NASH and NAFLD: emerging drugs, therapeutic targets and translational and clinical challenges.
Expert Opin Investig Drugs, 29 (2): 87. [PMID:31984804]
2. Alkhouri N, Lawitz E, Noureddin M, DeFronzo R, Shulman GI. (2020)
GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH).
Expert Opin Investig Drugs, 29 (2): 135-141. [PMID:31519114]
3. Harriman G, Greenwood J, Bhat S, Huang X, Wang R, Paul D, Tong L, Saha AK, Westlin WF, Kapeller R et al.. (2016)
Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats.
Proc Natl Acad Sci USA, 113 (13): E1796-805. [PMID:26976583]
4. Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, Wang L, Harting E, Tarrant JM, McColgan BJ et al.. (2018)
GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease.
Gastroenterology, 155 (5): 1463-1473.e6. [PMID:30059671]
5. Matsumoto M, Yashiro H, Ogino H, Aoyama K, Nambu T, Nakamura S, Nishida M, Wang X, Erion DM, Kaneko M. (2020)
Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis.
PLoS ONE, 15 (1): e0228212. DOI: 10.1371/journal.pone.0228212 [PMID:31990961]