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

Uto, Yoshikazu; Ueno, Yuko; Kiyotsuka, Yohei; Miyazawa, Yuriko; Kurata, Hitoshi; Ogata, Tsuneaki; Yamada, Makiko; Deguchi, Toshio; Konishi, Masahiro; Takagi, Toshiyuki; Wakimoto, Satoko; Ohsumi, Jun

doi:10.1016/j.ejmech.2010.07.044

Cited by 30 publications

(11 citation statements)

References 41 publications

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“…Furthermore, animal studies have shown that SCD-derived palmitoleate (16:1n-7) participates as a blood-borne messenger in the control of energy homeostasis and insulin resistance [27]. Because of these discoveries, SCD has recently emerged as a possible target for the treatment of diabetes, hyperlipidemia and obesity [28], [29], [30].…”

Section: Discussionmentioning

confidence: 99%

Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

et al. 2011

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The molecular bases of Alzheimer's disease (AD) remain unclear. We used a lipidomic approach to identify lipid abnormalities in the brains of subjects with AD (N = 37) compared to age-matched controls (N = 17). The analyses revealed statistically detectable elevations in levels of non-esterified monounsaturated fatty acids (MUFAs) and mead acid (20:3n-9) in mid-frontal cortex, temporal cortex and hippocampus of AD patients. Further studies showed that brain mRNAs encoding for isoforms of the rate-limiting enzyme in MUFAs biosynthesis, stearoyl-CoA desaturase (SCD-1, SCD-5a and SCD-5b), were elevated in subjects with AD. The monounsaturated/saturated fatty acid ratio (‘desaturation index’) – displayed a strong negative correlation with measures of cognition: the Mini Mental State Examination test (r = −0.80; P = 0.0001) and the Boston Naming test (r = −0.57; P = 0.0071). Our results reveal a previously unrecognized role for the lipogenic enzyme SCD in AD.

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Section: Discussionmentioning

confidence: 99%

Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

et al. 2011

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confidence: 99%

“…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. [19][20][21][22][23] In the present study, we evaluated the effects of a benzoylpiperidine-based SCD-1 inhibitor on development of NASH.Methionine and choline-deficient (MCD) diet model is one of the most useful NASH models. 24) We previously reported that rat α1 type I collagen promoter-luciferase transgenic (Col1a1-Luc T g ) rats were an appropriate model for sensitively evaluating the fibrosis of kidney and various organs in a short-term period.…”

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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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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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“…In first step the ester ethyl 2-(2-pyridylacetate) was transformed into 2-(pyridin-2-yl)acetohydrazide (A) [ 35 , 36 ]. This was a starting material to obtain the 2-pyridylacetate thiosemicarbazide and oxazole derivatives.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Activities of Ethyl 2-(2-pyridylacetate) Derivatives Containing Thiourea, 1,2,4-triazole, Thiadiazole and Oxadiazole Moieties

et al. 2017

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Thirty six novel heterocyclic derivatives of ethyl 2-(2-pyridylacetate) were efficiently synthesized. The new compounds involve the linkage of a 2-pyridyl ring with thiosemicarbazide (compounds 1–7), 1,2,4-triazole (compounds 1a–7a), 1,3,4-thiadiazole (compounds 1b–7b), and 1,3,4-oxadiazole (compounds 1f–7f) moieties. The last group of compounds 1e–7e involves the connection of a 2-pyridyl ring with 1,2,4-triazole and thiourea. 1H-NMR, 13C-NMR and MS methods were used to confirm the structures of the obtained derivatives. The molecular structures of 3, 3b, 7a and 7f were further confirmed by X-ray crystallography. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram-negative rods and Candida albicans. In addition, the obtained compounds were tested for cytotoxicity and antiviral activity against HIV-1.

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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

Cited by 30 publications

References 41 publications

Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

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

Synthesis and Biological Activities of Ethyl 2-(2-pyridylacetate) Derivatives Containing Thiourea, 1,2,4-triazole, Thiadiazole and Oxadiazole Moieties

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