Novel benzoylpiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide and its plasma triglyceride-lowering effects in Zucker fatty rats

Uto, Yoshikazu; Ogata, Tsuneaki; Kiyotsuka, Yohei; Ueno, Yuko; Miyazawa, Yuriko; Kurata, Hitoshi; Deguchi, Toshio; Watanabe, Nobuaki; Konishi, Masahiro; Okuyama, Ryo; Kurikawa, Nobuya; Takagi, Toshiyuki; Wakimoto, Satoko; Ohsumi, Jun

doi:10.1016/j.bmcl.2009.10.101

Cited by 28 publications

(27 citation statements)

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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%

“…The detailed synthetic procedures, physicochemical properties and pharmacokinetic profile of the SCD-1 inhibitors with this structural motif have been previously reported. 21) Animals All experimental procedures were performed in accordance with the in-house guideline of the International Animal Care and Use Committee of Daiichi Sankyo Co., Ltd. Col1a1-Luc T g rats were generated by a previously reported method, and bred in Japan SLC Inc. (Shizuoka, Japan). 25) C57BL/6J mice were purchased from Charles River Laboratories Japan, Inc. (Yokohama, Japan).…”

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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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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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“…The optimization process led to compound 7 with IC 50 values of 28 nM (enzymatic) and 43 nM (293A cell) versus hSCD1. 52 In a PK-PD study, 7 inhibited the conversion of 14 C-stearate to 14 C-oleate in the liver of db/db mice with an ED 50 of 3 mg/kg. The combination of hydroxy and 3-pyridyl groups improved the microsomal stability and oral absorption of 7 in mice (F 5 68%, AUC of 7.8 mM?h at 20 mg/kg dosing).…”

Section: Pyridazine Carboxamides 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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“…The separated organic layer was washed with brine and water, dried (MgSO 4 ), filtered and concentrated to dryness. The product was purified by column chromatography (DCM) and was collected as colorless oil (1. (22). Lithium aluminium hydride (0.031 g, 0.81 mmol) was dissolved in THF (5 ml).…”

Section: -Fluorodihydrofuran-2(3h)-one (18)mentioning

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Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography

et al. 2015

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Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood-brain barrier is a pathological hallmark of many neurological diseases, and the resulting multiple drug resistance represents a major clinical challenge. Noninvasive imaging of transporter activity can help to clarify the underlying mechanisms of drug resistance and facilitate diagnosis, patient stratification, and treatment monitoring. We have developed a metabolically activated radiotracer for functional imaging of P-gp/BCRP activity with positron emission tomography (PET). In preclinical studies, the tracer showed excellent initial brain uptake and clean conversion to the desired metabolite, although at a sluggish rate. Blocking with P-gp/BCRP modulators led to increased levels of brain radioactivity; however, dynamic PET did not show differential clearance rates between treatment and control groups. Our results provide proof-of-concept for development of prodrug tracers for imaging of P-gp/BCRP function in vivo but also highlight some challenges associated with this strategy.

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Novel benzoylpiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide and its plasma triglyceride-lowering effects in Zucker fatty rats

Cited by 28 publications

References 27 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

Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography

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