Effects of an anti-oxidative ACAT inhibitor on apoptosis/necrosis and cholesterol accumulation under oxidative stress in THP-1 cell-derived foam cells

Q3 · MEDICINE

Article

Author: Hiroaki Shirahase ; Kazuyoshi Kurahashi ; Kazuyoshi Kunishiro ; Tomohiro Miike ; Mamoru Kanda ; Hiroshi Jino

THP-1 cell-derived foam cells were exposed to oxidative stress through combined treatment with acetylated LDL (acLDL) and copper ions (Cu2+). The foam cells showed caspase-dependent apoptotic changes on exposure to oxidative stress for 6 h, and necrotic changes with the leakage of LDH after 24 h. KY-455, an anti-oxidative ACAT inhibitor, and ascorbic acid (VC) but not YM-750, an ACAT inhibitor, prevented apoptotic and necrotic changes. These preventive effects of KY-455 and VC were accompanied by the inhibition of lipid peroxidation in culture medium containing acLDL and Cu2+, suggesting the involvement of oxidized acLDL in apoptosis and necrosis. Foam cells accumulated esterified cholesterol (EC) for 24 h in the presence of acLDL without Cu2+, which was suppressed by KY-455 and YM-750. Foam cells showed necrotic changes and died in the presence of acLDL and Cu2+. KY-455 but not YM-750 prevented cell death and reduced the amount of EC accumulated. The foam cells treated with VC further accumulated EC without necrotic changes for 24 h even in the presence of acLDL and Cu2+. YM-750 as well as KY-455 inhibited lipid accumulation when co-incubated with VC in foam cells exposed to oxidative stress. It is concluded that an anti-oxidative ACAT inhibitor or the combination of an antioxidant and an ACAT inhibitor protects foam cells from oxidative stress and effectively reduces cholesterol levels, which would be a promising approach in anti-atherosclerotic therapy.

01 Jan 2000·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Bioavailable Acyl-CoA. Cholesterol Acyltransferase Inhibitor with Anti-peroxidative Activity. Synthesis and Biological Activity of Novel Indolinyl Amide and Urea Derivatives.

Q4 · MEDICINE

Article

Author: Kurahashi, Kazuyoshi ; Kamiya, Shoji ; Nakamura, Shohei ; Matsui, Hiroshi ; Kanda, Mamoru ; Yoshimi, Akihisa ; Kasai, Masayasu ; Shirahase, Hiroaki ; Takahashi, Kenji

We synthesized a series of indoline derivatives with an amide or urea moiety and examined their inhibitory effects on acyl-CoA:cholesterol acyltransferase (ACAT) activity, lipid-peroxidation and serum cholesterol levels in experimental animals. Among the derivatives synthesized, a series of N-(1-alkyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamides++ + potently inhibited rabbit intestinal ACAT activity and lipid-peroxidation of rat brain homogenate. The effect on ACAT activity was related to the length of the alkyl chain at the 1-position of indoline. N-(4,6-Dimethyl-1-octylindolindolin-7-yl)-2,2-dimethylpropanami de hydrochloride (55) showed inhibitory effects on intestinal and hepatic ACAT activity slightly weaker than those of YM-750, and an inhibitory effect on low density lipoprotein (LDL)-peroxidation similar to that of probucol. Compound 55 also reduced serum cholesterol at 10 mg/kg/d in hyperlipidemic rats and 20 mg/kg/d in normolipidemic hamsters. The plasma concentration of 55 reached 716 ng/ml in dogs (10 mg/kg, p.o.), which is an effective concentration against hepatic ACAT activity and LDL-peroxidation. In conclusion, compound 55 is a novel bioavailable ACAT inhibitor with anti-peroxidative activity and is thus a promising anti-atherosclerotic and anti-hyperlipidemic drug. Indoline proved to be a useful pharmacophore for molecular design of new anti-peroxidative drugs.

01 Mar 1995·Biochemical PharmacologyQ2 · MEDICINE

N-[2-[N′-pentyl-(6,6-dimethyl-2,4-heptadiynyl) amino]ethyl]-(2-methyl-1-naphthylthio)acetamide (FY-087)

Q2 · MEDICINE

Article

Author: Yoshikazu Iwasawa ; Yoshio Sawazaki ; Hiromi Hattori ; Yasufumi Nagata ; Toshio Kamei ; Mari Yonemoto ; Akiko Shimizu-Nagumo

FY-087 (N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]- (2-methyl-1-naphthylthio)acetamide) was found to be a competitive inhibitor of human microsomal acyl coenzyme A:cholesterol acyltransferase (ACAT) with an IC50 value of 0.11 microM. Under our assay conditions, other ACAT inhibitors tested, specifically YM-750, E-5324, and melinamide, all of which are now in phase I clinical trials or in clinical use in Japan, inhibited this enzyme with IC50 values of 0.18, 0.14, and 3.2 microM, respectively. FY-087 also inhibited ACAT in acetyl-low density lipoprotein loaded human macrophages (THP-1 cells) with an IC50 of 0.17 microM. Following the oral administration of FY-087 (30 mg/kg) to rats, the plasma concentration of FY-087 reached 0.42 microgram/mL after 2 hr. This concentration of FY-087 was enough to inhibit blood vessel ACAT activity. Cholesterol-lowering and anti-atherogenic effects of FY-087 were examined using C57BL/6J mice fed an atherogenic diet. In this mouse model, treatment with FY-087 (28 mg/kg) inhibited the increase in plasma cholesterol levels by about 20% and decreased the hepatic accumulation of free and esterified cholesterol by 61 and 67%, respectively. FY-087 also significantly inhibited the atherogenic diet-induced increase in the fatty-streak lesion area of the proximal aorta by 57% in C57BL/6J mice. These results indicate that FY-087 is not only a therapeutically bioavailable ACAT inhibitor that lowers plasma cholesterol levels, but also an effective anti-atherogenic agent in mice fed an atherogenic diet.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 1	JP	Yamanouchi Pharmaceutical Co. Ltd. /Over-the-Counter Phar Bus	-
Hyperlipidemias	Phase 1	-	Astellas Pharma, Inc.	-

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