Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

Koltun, Dmitry O.; Vasilevich, Natalya I.; Parkhill, Eric Q.; Glushkov, Andrei I.; Zilbershtein, Timur M.; Mayboroda, Elena; Boze, Melanie A.; Cole, Andrew G.; Henderson, Ian; Zautke, Nathan A.; Brunn, Sandra A.; Chu, Nancy; Hao, Jia; Mollova, Nevena; Leung, Kwan; Chisholm, Jeffrey W.; Zablocki, Jeff

doi:10.1016/j.bmcl.2009.04.004

Cited by 39 publications

(17 citation statements)

References 22 publications

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“…It was reported that genetic deletion or pharmacological inhibition of SCD-1 prevented some metabolic disorders including obesity, insulin resistance and dyslipidemia. [11][12][13][14][16][17][18][33][34][35] The SCD-1 inhibitor may have an advantage for NASH/NAFLD other than direct effects on hepatic triglyceride synthesis.…”

Section: -23)mentioning

confidence: 99%

“…[12][13][14][15] Additionally, pharmacological inhibition of SCD-1 also improved hepatic lipid accumulation and metabolic disorders. [16][17][18] On the other hand, it was poorly understood whether SCD-1 inhibition protects crucial pathological observations of NASH such as liver injury, inflammation and fibrosis. We previously reported that novel SCD-1 inhibitors with some scaffolds were obtained, and they showed potent inhibition of SCD-1 activity in vitro and in vivo.…”

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confidence: 99%

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A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

Kurikawa

Takagi

Wakimoto

et al. 2013

Biological & Pharmaceutical Bulletin

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Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the biosynthesis of monounsaturated fatty acids, and their abnormality is possibly responsible for obesity, insulin resistance, hepatic steatosis and nonalcoholic steatohepatitis (NASH). A novel SCD-1 inhibitor, N-(2-hydroxy-2-phenylethyl)-6-[4-(2-methyl benzoyl) piperi din-1-yl]pyridazine-3-carboxamide, has been obtained. The compound inhibited liver SCD-1 activity and increased liver triglyceride accumulation in mice fed with non-fat, high-sucrose diets. In order to evaluate the effects of the SCD-1 inhibitor on NASH development, rats were fed with lipogenic methionine and choline-deficient (MCD) diets for 8 weeks. The SCD-1 inhibitor was administered once-daily at a dose of 30 or 100 mg/kg/d by oral gavage. Administration of a high dose of the SCD-1 inhibitor decreased triglyceride accumulation in the liver of NASH rats by 80%. Administration of a high dose of the SCD-1 inhibitor attenuated the increase of aspartate aminotransferase (AST) and alanine transaminase (ALT) by 86% and 78%, respectively. Hepatic steatosis, hepatocellular degeneration and inflammatory cell infiltration were histologically observed in the liver of NASH rats, and administration of the SCD-1 inhibitor ameliorated these crucial observations in NASH. In summary, an SCD-1 inhibitor ameliorated hepatic triglyceride accumulation, liver injury, hepatocellular degeneration and inflammation in experimental NASH models. These results suggest that SCD-1 maybe a promising target for the treatment of NASH.Key words stearoyl-CoA desaturase-1; steatohepatitis; methionine choline-deficient diet Nonalcoholic fatty liver disease (NAFLD), which is identified with excess lipid accumulation in the liver, is strongly associated with obesity, insulin resistance, hypertension, dyslipidemia and metabolic syndrome.1,2) Most NAFLD are in prognosis, although some of these progress to nonalcoholic steatohepatitis (NASH), which is defined as a histological observation of hepatocellular degeneration, inflammation and fibrosis in liver with steatosis. Finally, some NASH patients progress to liver cirrhosis and hepatocellular carcinomas, which are at the end-stage of liver disease. It is postulated that 3 to 6% of the population indicates NASH in the United States, and it is expected that the population of NASH patients will increase in the future.2) Therefore, there is a pressing need for developing a therapeutic drug to treat NASH. There are however, no therapeutic drugs approved for treating NASH patients, although some clinical pilot studies have indicated that some compounds, including insulin sensitizers, anti-dyslipidemic drugs, anti-hypertensive drugs, anti-obesity drugs and antioxidants, were effective for NASH/NAFLD. 3-9)Stearoyl-CoA desaturase (SCD) is an endoplasmic reticulum enzyme that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acyl-CoAs. 10)SCD in conjunction with the reduced nicotinamide adenine dinucleotide phosphate (NADPH), the flavoprotein cytochrome b5 reducta...

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Section: -23)mentioning

confidence: 99%

mentioning

confidence: 99%

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

Kurikawa

Takagi

Wakimoto

et al. 2013

Biological & Pharmaceutical Bulletin

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“…A highly significant reduction in SCD product fatty acids in both plasma and liver was observed, based on DI change following bid dosing of 20 for 5 days. 65 Even though compound 20 was claimed to be liver preferred, the 3-5-fold separation from plasma concentration was not expected to translate into a significant therapeutic window.…”

Section: Pharmacology and Adverse Eventsmentioning

confidence: 99%

“…It has IC 50 values of 267 nM (rSCD) and 79 nM (HepG2), and reasonable exposure (AUC 5 935 ng?h/mL) and high oral bioavailability (90%). 65 Merging select structural features of the two series led to the discovery of compound 21 (CVT-12,012), which is highly potent in a human cell-based (HEPG2) SCD assay (IC 50 5 6 nM). 66 This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times versus plasma).…”

Section: Pteridinones and Related Analogsmentioning

confidence: 99%

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Liu¹

2012

Drug Discovery

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“…1). CV Therapeutics (Gilead) reported 2-oxo-2H-quinoxalin-based structures [22] and subsequently disclosed the structures of CVT-11,563 (5) [23] and CVT-12,012 (6) [24]. A class of aminoimidazole analogs, represented by DSR-4029 (7) [25], was revealed by DainipponSumitomo.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs

Uto¹,

Ueno²,

Kiyotsuka³

et al. 2010

European Journal of Medicinal Chemistry

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Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

Cited by 39 publications

References 22 publications

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs

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