Synthesis, X-ray crystal structure, and biological activity of FR186054, a novel, potent, orally active inhibitor of acyl-CoA:cholesterol O -acyltransferase (ACAT) bearing a pyrazole ring

Terasawa, Takeshi; Hagihara, Hiroyuki; Kinoshita, Takayoshi; Sakuma, Yoh; Ishibe, Noriko; Sawada, Masae; Takasugi, Hisashi; Tanaka, Hirokazu

doi:10.1016/s0960-894x(97)10191-3

Cited by 11 publications

(15 citation statements)

References 22 publications

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“…Likewise, using methyl sulfonyl hydrazine to react with enaminone 1 a did not provide the expected product, either. Additionally, the reaction using simple phenyl hydrazine with enaminone 1 a was also conducted under the standard conditions, but only pyrazole resulting from simple and classical hydrazine/enaminone condensation [19] was observed.…”

Section: Resultsmentioning

confidence: 99%

Transition Metal‐free C−H Sulfonylation and Pyrazole Annulation Cascade for the Synthesis of 4‐Sulfonyl Pyrazoles

2020

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A practical protocol for the synthesis of 4-sulfonyl pyrazoles via the reactions of readily available N,N-dimethyl enaminones and sulfonyl hydrazines has been developed via the catalysis of molecular iodine in the presence of TBHP and NaHCO 3 at room temperature. The pyrazole products have been constructed via the tandem C(sp 2 )À H sulfonylation and a pyrazole annulation without employing any transition metal catalyst or reagent, thus providing a practical new method for the synthesis of the novel pyrazoles bearing a sulfonyl side chain in the heterocycle.

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Section: Resultsmentioning

confidence: 99%

Transition Metal‐free C−H Sulfonylation and Pyrazole Annulation Cascade for the Synthesis of 4‐Sulfonyl Pyrazoles

2020

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“…This compound was redesigned by inserting a pyrazole ring, which increased its polarity without compromising its ACAT inhibitory properties (87). Moreover, this new compound showed a reduced adrenal toxicity.…”

Section: Solubility and Bioavailability Issues Regarding Acat Inhibitorsmentioning

confidence: 99%

Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

2005

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Acyl-coenzyme A:cholesterol transferase (ACAT) is an integral membrane protein localized in the endoplasmic reticulum. ACAT catalyzes the formation of cholesteryl esters from cholesterol and fatty acyl coenzyme A. The cholesteryl esters are stored as cytoplasmic lipid droplets inside the cell. This process is very important to the organism as high cholesterol levels have been associated with cardiovascular disease. In mammals, two ACAT genes have been identified, ACAT1 and ACAT2. ACAT1 is ubiquitous and is responsible for cholesteryl ester formation in brain, adrenal glands, macrophages, and kidneys. ACAT2 is expressed in the liver and intestine. The inhibition of ACAT activity has been associated with decreased plasma cholesterol levels by suppressing cholesterol absorption and by diminishing the assembly and secretion of apolipoprotein B-containing lipoproteins such as very low density lipoprotein (VLDL). ACAT inhibition also prevents the conversion of macrophages into foam cells in the arterial walls, a critical event in the development of atherosclerosis. This review paper will focus on the role of ACAT in cholesterol metabolism, in particular as a target to develop novel therapeutic agents to control hypercholesterolemia, atherosclerosis, and Alzheimer's disease.

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“…Using cellular systems, it has been demonstrated that ACAT1 inhibitors can cause undesirable accumulation of cellular free cholesterol leading to apoptosis (Feng et al 2003; Warner et al 1995). Furthermore, a number of ACAT inhibitors, some of which are nonspecific inhibitors of ACAT1/ACAT2, have induced adrenal toxicities while others, such as Avasimibe, which has since failed in clinical development, have been described as lacking significant adrenal toxicity (Reindel, Dominick, and Krause 1992; Reindel et al 1994; Wolfgang et al 1995; Riddell et al 1996; Wilde et al 1996; Tanaka et al 1998; Sliskovic et al 1998; Sliskovic, Picard, and Krause 2002; Robertson, Breider, and Milad 2001). It is noteworthy that to date, no ACAT inhibitor has successfully emerged as a safe and efficacious therapy from clinical research where studies in humans showed that several drugs lacked efficacy for lowering cholesterol (Farese 2006).…”

Section: Introductionmentioning

confidence: 99%

ACAT-selective and Nonselective DGAT1 Inhibition

et al. 2013

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Acyl-coenzyme A: cholesterol O-Acyltransferase (ACAT) and Acyl-coenzyme A: diacylglycerol O-acyltransferase (DGAT) enzymes play important roles in synthesizing neutral lipids, and inhibitors of these enzymes have been investigated as potential treatments for diabetes and other metabolic diseases. Administration of a Acyl-coenzyme A: diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor with very limited cellular selectivity over ACAT resulted in significant adrenocortical degenerative changes in dogs. These changes included macrosteatotic vacuolation associated with adrenocyte cell death in the zonae glomerulosa and fasciculata and minimal to substantial mixed inflammatory cell infiltration and were similar to those described previously for some ACAT inhibitors in dogs. In the mouse, similar but only transient adrenocortical degenerative changes were seen as well as a distinctive nondegenerative reduction in cortical fine vacuolation. In the marmoset, only the distinctive nondegenerative reduction in cortical fine vacuolation was observed, suggesting that the dog, followed by the mouse, is the most sensitive species for cortical degeneration. Biochemical analysis of adrenal cholesterol and cholesteryl ester indicated that the distinctive reduction in cortical fine vacuolation correlated with a significant reduction in cholesteryl ester in the mouse and marmoset, whereas no significant reduction in cholestryl ester, but an increase in free cholesterol was observed in dogs. Administration of a DGAT1 inhibitor with markedly improved selectivity over ACAT to the marmoset and the mouse resulted in no adrenal pathology at exposures sufficient to cause substantial DGAT1 but not ACAT inhibition, thereby implicating ACAT rather than DGAT1 inhibition as the probable cause of the observed adrenal changes. Recognizing that the distinctive nondegenerative reduction in cortical fine vacuolation in the mouse could be used as a histopathological biomarker for an in vivo model of the more severe changes observed in dogs, the mouse has subsequently been used as a model to select DGAT1 inhibitors free of adrenocortical toxicity.

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Synthesis, X-ray crystal structure, and biological activity of FR186054, a novel, potent, orally active inhibitor of acyl-CoA:cholesterol O -acyltransferase (ACAT) bearing a pyrazole ring

Cited by 11 publications

References 22 publications

Transition Metal‐free C−H Sulfonylation and Pyrazole Annulation Cascade for the Synthesis of 4‐Sulfonyl Pyrazoles

Transition Metal‐free C−H Sulfonylation and Pyrazole Annulation Cascade for the Synthesis of 4‐Sulfonyl Pyrazoles

Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

ACAT-selective and Nonselective DGAT1 Inhibition

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