The flexible three-component reaction of lithiated alkoxyallenes with nitriles and carboxylic acids provided a series of highly functionalised beta-alkoxy-beta-ketoenamide derivatives. Upon base induced cyclisation and conversion to 4-pyridyl nonaflates various palladium-catalysed coupling reactions could be employed. The efficacy of this approach to functionalised pyridine derivatives was demonstrated by a fairly short route to a key intermediate suitable for a Glenvastatin synthesis. After Sonogashira couplings of alkynes with 4-pyridyl nonaflates subsequent cyclisations led to highly fluorescent [2,3c]furopyridine derivatives, whereas Suzuki reactions afforded 4-pyridyl stilbenes and by photocyclisation a highly substituted benzoisoquinoline derivative.

2004-01-01·Pharmacology4区 · 医学

Effects of HR780, a Novel 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, in Watanabe Heritable Hyperlipidemic Rabbits and Cholesterol-Fed Rabbits

4区 · 医学

Article

作者: Oshima, Kenichi ; Wajima, Teruaki ; Makita, Shigeki

The aim of this study was to evaluate the effects of (+)-(E)-6S-(2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (HR780), a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on hypercholesterolemia in Watanabe heritable hyperlipidemic (WHHL) rabbits and rabbits fed a diet with 1% cholesterol, in comparison with the effects of simvastatin. Each drug was administered orally to WHHL rabbits for 24 weeks and to 1% cholesterol-fed rabbits for 10 weeks. In WHHL rabbits, HR780 at doses of 1, 2.5 and 5 mg/kg/day reduced the plasma total cholesterol level by 15, 24 and 20%, respectively. In contrast, simvastatin at 5 mg/kg/day lowered the level by 23%. In 1% cholesterol-fed rabbits, HR780 (1 and 2.5 mg/kg/day) was found to inhibit the increases in the plasma total cholesterol and phospholipid levels and liver cholesterol contents in a dose-dependent manner. Simvastatin (5 mg/kg/day) also inhibited their increase. Neither HR780 nor simvastatin increased the contents of cholesterol and total bile acid in the gallbladder bile. In conclusion, long-term treatment with HR780 reduced the plasma cholesterol level in WHHL rabbits and 1% cholesterol-fed rabbits, and decreased the liver cholesterol contents in 1% cholesterol-fed rabbits.

2003-12-01·Clinical and Experimental Pharmacology and Physiology4区 · 医学

Direct vascular effects of HR780, a novel 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor

4区 · 医学

Article

作者: Teruaki Wajima ; Kenichi Oshima ; Shigeki Makita

Summary1. We have examined the effects of HR780, a novel 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor, on porcine endothelial cell (EC) injury induced by xanthine (X)/xanthine oxidase (XO), a source of superoxide anion. Furthermore, the effects of HR780 on platelet‐derived growth factor (PDGF)‐induced migration and fetal calf serum (FCS)‐induced proliferation of rabbit smooth muscle cells (SMC) were investigated.2. Probucol, at 10 µmol/L, significantly (P < 0.001) and completely suppressed lactate dehydrogenase leakage induced by X/XO. At 10 µmol/L, HR780 significantly (P = 0.010) inhibited X/XO‐induced EC injury.3. HR780 dose‐dependently inhibited PDGF‐induced SMC migration and FCS‐induced SMC proliferation. The addition of mevalonate completely abolished the inhibitory effect of HR780 on SMC proliferation. Another HMG‐CoA reductase inhibitor, simvastatin (0.1–100 µmol/L), also inhibited the migration and proliferation responses as potently as HR780. In contrast, pravastatin (0.1–100 µmol/L) did not show any effects.4. This in vitro study provides the first evidence that HR780 protects the vascular endothelium from oxidant stress and inhibits the migration and proliferation of SMC.

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