ND-630 - CAS 1434635-54-7
Catalog number: B0084-007342
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C28H31N3O8S
Molecular Weight:
569.63
COA:
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Targets:
ACC
Description:
ND-630, also called as NDI 010976, is a highly selective, reversible inhibitor of acetyl-CoA carboxylase (ACC) and had IC50 values of 2 and 7 nM for ACC1 and 2, respectively, EC50 values in HepG2 serum free and 10% serum of 9 and 66 nM, respectively, and 2-fold C2C12 fatty acid oxidation (FAOxn) stimulation at 200 nM.
Ordering Information
Catalog Number Size Price Stock Quantity
B0084-007342 10 mg $198 In stock
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Synonyms:
2-[1-[(2R)-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
Solubility:
DMSO: ≥ 50 mg/mL
Storage:
Store in a cool and dry place (or refer to the Certificate of Analysis).
MSDS:
Inquire
Boiling Point:
779.0±70.0 ℃ at 760 Torr
Density:
1.42±0.1 g/cm3
InChIKey:
ZZWWXIBKLBMSCS-FQEVSTJZSA-N
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
Canonical SMILES:
CC1=C(SC2=C1C(=O)N(C(=O)N2CC(C3=CC=CC=C3OC)OC4CCOCC4)C(C)(C)C(=O)O)C5=NC=CO5
1.Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis.
Lawitz EJ;Coste A;Poordad F;Alkhouri N;Loo N;McColgan BJ;Tarrant JM;Nguyen T;Han L;Chung C;Ray AS;McHutchison JG;Subramanian GM;Myers RP;Middleton MS;Sirlin C;Loomba R;Nyangau E;Fitch M;Li K;Hellerstein M Clin Gastroenterol Hepatol. 2018 Apr 26. pii: S1542-3565(18)30404-X. doi: 10.1016/j.cgh.2018.04.042. [Epub ahead of print]
BACKGROUND & AIMS: ;Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.;METHODS: ;In an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis.;RESULTS: ;The contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .
2.Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats.
Harriman G;Greenwood J;Bhat S;Huang X;Wang R;Paul D;Tong L;Saha AK;Westlin WF;Kapeller R;Harwood HJ Jr Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1796-805. doi: 10.1073/pnas.1520686113. Epub 2016 Mar 14.
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.
3.GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients with Nonalcoholic Fatty Liver Disease.
Loomba R;Kayali Z;Noureddin M;Ruane P;Lawitz EJ;Bennett M;Wang L;Harting E;Tarrant JM;McColgan BJ;Chung C;Ray AS;Subramanian GM;Myers RP;Middleton MS;Lai M;Charlton M;Harrison SA Gastroenterology. 2018 Jul 27. pii: S0016-5085(18)34815-7. doi: 10.1053/j.gastro.2018.07.027. [Epub ahead of print]
BACKGROUND AND AIMS: ;De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-CoA carboxylase in liver, in a phase 2, randomized, placebo-controlled trial of patients with NASH.;METHODS: ;We analyzed data from 126 patients with hepatic steatosis ≥8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness ≥2.5 kPa, based on magnetic resonance elastography measurement, or historical biopsy consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 (20 mg), GS-0976 (5mg), or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relationship between dose and efficacy.;RESULTS: ;A ≥30% relative decrease from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given 20 mg GS-0976 (P=.004 vs placebo), 23% given 5 mg GS-0976 (P=.
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CAS 1434635-54-7 ND-630

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