pitavastatin and mevalonolactone

A novel series of 2-cyclopropyl-4-thiophenyl quinoline-based mevalonolactones were synthesized from the substituted anilines by several reactions. Among them, (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(4-fluoro-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1d), (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1f) and (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4,7-di(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1q) showed potent HMG-CoA reductase inhibitory activity comparable with pitavastatin.

Topics: Acyl Coenzyme A; Animals; Cyclopropanes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Magnetic Resonance Spectroscopy; Mevalonic Acid; Quinolines; Rats; Spectrometry, Mass, Electrospray Ionization; Sulfhydryl Compounds

Neural apoptosis-regulated convertase (NARC)-1 is the newest member of the proprotein convertase family implicated in the cleavage of a variety of protein precursors. The NARC-1 gene, PCSK9, has been identified recently as the third locus implicated in autosomal dominant hypercholesterolemia (ADH). The 2 other known genes implicated in ADH encode the low-density lipoprotein receptor and apolipoprotein B. As an approach toward the elucidation of the physiological role(s) of NARC-1, we studied its transcriptional regulation.. Using quantitative RT-PCR, we assessed NARC-1 regulation under conditions known to regulate genes involved in cholesterol metabolism in HepG2 cells and in human primary hepatocytes. We found that NARC-1 expression was strongly induced by statins in a dose-dependent manner and that this induction was efficiently reversed by mevalonate. NARC-1 mRNA level was increased by cholesterol depletion but insensitive to liver X receptor activation. Human, mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol regulation: a sterol regulatory element (SRE) and an Sp1 site.. PCSK9 regulation is typical of that of the genes implicated in lipoprotein metabolism. In vivo, PCSK9 is probably a target of SRE-binding protein (SREBP)-2.

Topics: Alitretinoin; Animals; Atorvastatin; Base Sequence; Cell Line; Cholesterol; Consensus Sequence; DNA-Binding Proteins; Gene Expression Regulation; Hepatocytes; Heptanoic Acids; Homeostasis; Humans; Hydroxycholesterols; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver X Receptors; Lovastatin; Mevalonic Acid; Mice; Orphan Nuclear Receptors; Promoter Regions, Genetic; Proprotein Convertase 9; Proprotein Convertases; Pyridines; Pyrroles; Quinolines; Rats; Receptors, Cytoplasmic and Nuclear; Regulatory Sequences, Nucleic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Alignment; Sequence Homology, Nucleic Acid; Serine Endopeptidases; Simvastatin; Sp1 Transcription Factor; Species Specificity; Sterol Regulatory Element Binding Protein 2; Transcription Factors; Tretinoin

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress smooth muscle cell growth and arterial neointimal thickening. In this study, to elucidate the potency and mechanisms of NK-104 ((+)-monocalcium bis[(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate], CAS 147526-32-7) in neointimal thickening, the effect of NK-104 on the neointimal thickening, Br-dU-labeled cell number and extracellular matrix immunohistochemistry were examined in balloon-injured rabbit carotid artery. NK-104 suppressed the neointimal thickening dose-dependently, and the suppression was 69.5% at 1.0 mg/kg. NK-104 suppressed the intimal total and Br-dU-labeled cell number. Fibronectin and type I collagen were observed in 81% and 38% of the total intimal area in the control arteries, respectively, and the areas occupied by fibronectin and type I collagen were significantly decreased by 1.0 mg/kg NK-104 to 39% and 22%, respectively. The decrease in fibronectin per cell was more potently demonstrated. Aortic total and activated TGF-beta contents that were markedly increased in the injured artery were increased further by NK-104. NK-104 concentration-dependently suppressed fibronectin content of the basement lesion in rabbit primary cultured smooth muscle cells. These findings suggest that NK-104 suppresses balloon-injury-induced neointimal thickening through inhibition of intimal smooth muscle cell growth and extracellular matrix accumulation.

Topics: Animals; Aorta; Carotid Arteries; Carotid Artery Injuries; Catheterization; Cell Division; Cell Line; DNA; Eukaryotic Cells; Extracellular Matrix; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Mevalonic Acid; Muscle, Smooth, Vascular; Pravastatin; Quinolines; Rabbits; Simvastatin; Transforming Growth Factor beta; Tunica Intima; Tunica Media