Synthetic HMG-CoA Reductase Inhibitor Research Articles

A preliminary report of the safety and efficacy of fluvastatin for hypercholesterolemia in renal transplant patients receiving cyclosporine

Hypercholesterolemia is common following renaltransplantation and undoubtedly contributes to morbidity and mortality due to occlusive atherosclerosis in these patients. Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are more tolerable as low density lipoprotein cholesterol (LDL-C)-lowering agents than other classes of drugs, their use in transplant patients has been limited due to potentially serious interactions with cyclosporine. Fluvastatin is the first wholly synthetic HMG-CoA reductase inhibitor. Because it has a shorter half-life and greater protein-binding capacity than other drugs of this class and has no active circulating metabolites, fluvastatin may be safer than other HMG-CoA reductase inhibitors in this group of patients. To study this question, 19 renal transplant recipients (age, 21–70 years) with hypercholesterolemia (LDL-C > 180 mg/dL; triglycerides <400 mg/liter) were entered into a 14-week active-treatment period with fluvastatin at 20 mg/day following dietary stabilization and a 3-week placebo washout period. Changes in LDL-C levels were compared with those obtained in control hypercholesterolemic subjects treated in the same way. The lipid-lowering ability of fluvastatin was not impaired in these patients, indicating a lack of interaction with cyclosporine. Mean liver enzyme levels, creatinine phosphokinase (CPK), and creatine did not change significantly from baseline. Two subjects experienced myalgias without CPK elevations, and another subject experienced an asymptomatic increase in CPK to >10 times the upper limit of normal, related to exercise. In conclusion, fluvastatin safely and effectively lowers elevated LDL-C levels in renal transplant recipients.

Mevalonate is essential for growth of porcine and human vascular smooth muscle cells in vitro.

The effects of mevalonate depletion on growth and cell cycle kinetics of porcine and human vascular smooth muscle cells (SMC) were studied by growth curves and flow cytometric determination of cell cycle distribution. Porcine and human SMC were growth arrested by serum depletion for 48 h. Subsequently, they were stimulated to maximal growth and DNA synthesis by addition of serum. There was a concentration dependent decrease in the proliferation of human and porcine SMC, when cells were incubated in the presence of fluvastatin, a new, fully synthetic HMGCoA-reductase inhibitor. The reduction of cell number was significant with 10(-5) M and 10(-4)M fluvastatin. The highest concentration induced cell loss after prolonged incubation (> 4 days). The G/S-phase transition of human and porcine vascular SMC was reduced to 50% of controls by 10(-4) M fluvastatin as revealed by cell cycle analysis. The effects of fluvastatin on growth kinetics and cell cycle distribution could be completely reversed by the addition of 1 mM mevalonolactone. This indicates that the inhibitory effect of fluvastatin is caused by the inhibition of HMGCoA-reductase and depletion of mevalonate rather than being unspecific. Addition of LDL to supply cholesterol failed to support cell growth and transition of smooth muscle cells from G(zero)/G1-phase to S-phase, even though LDL was taken up by the cells as shown by confocal fluorescence microscopy. Neither did the addition of squalene or cholesterol to the culture medium normalize cell growth. It is concluded that nonsterol products that are synthesized from mevalonate are necessary for growth of smooth muscle cells. HMGCoA-reductase inhibitors like fluvastatin block the synthesis of these nonsterol precursors in human and porcine vascular SMC in vitro and are therefore growth inhibitory.

Clinical efficacy of fluvastatin, a new synthetic HMG-CoA reductase inhibitor, in long-term treatment of hyperlipidemia; results of a multicenter long-term study

Clinical efficacy of fluvastatin, a new synthetic HMG-CoA reductase inhibitor, in long-term treatment of hyperlipidemia; results of a multicenter long-term study

LS2904, a synthetic HMG-CoA reductase inhibitor: preliminary results on Watanabe atherosclerosis

LS2904, a synthetic HMG-CoA reductase inhibitor: preliminary results on Watanabe atherosclerosis

A double-blind controlled trial on the efficacy and safety of a new synthetic HMG-CoA reductase inhibitor, fluvastatin, with and without open-label niacin, in the treatment of hypercholesterolemia

A double-blind controlled trial on the efficacy and safety of a new synthetic HMG-CoA reductase inhibitor, fluvastatin, with and without open-label niacin, in the treatment of hypercholesterolemia

Carcinogenicity and Mutagenicity Studies with Fluvastatin, a New, Entirely Synthetic HMG-CoA Reductase Inhibitor

Carcinogenicity and Mutagenicity Studies with Fluvastatin, A New, Entirely Synthetic HMG-CoA Reductase Inhibitor. Robison, R. L, Suter, W, and Cox, R. H. (1994). Fundam. Appl. Toxicol. 23, 9-20.The HMG-CoA reductase inhibitors are a new and novel class of cholesterol-lowering agents which are widely used worldwide. Fluvastatin is the first entirely synthetic compound in this class and is structurally distinct from fungal metabolite derivatives which are already marketed. As the liver is the site of some toxic effects for these compounds, it was not entirely unexpected that liver cancer was found in rats and/or mice with the first three marketed compounds, lovastatin, pravastatin, and simvastatin. Four lifetime carcinogenicity studies (two rat and two mouse) did not give any evidence that fluvastatin induced liver tumors in rodents. Fluvastatin induced thyroid neoplasms in rats and forestomach papillomas in rodents, as other compounds in this pharmacologic class have also done.The genotoxic potential of fluvastatin has been assessed in vitro using Salmonella typhimurium, Escherichia coli (gene mutations), V79 Chinese hamster cells (HGPRT gene mutations, chromosomal aberrations), rat hepatocyte primary cultures (DNA repair), and BALB/3T3 cells (malignant transformations). Fluvastatin was also tested in vivo for clastogenicity using the mouse bone marrow micronucleus test and by performing a cytogenetic analysis in the rat bone marrow after acute and subacute treatment. In all seven assays fluvastatin was found to be free of any genotoxic potential.

The HMG-CoA Reductase Inhibitor Fluvastatin Inhibits Insect Juvenile Hormone Biosynthesis

Fluvastatin (Sandoz Compound XU 62-320), a synthetic HMG-CoA reductase inhibitor, was assayed in vitro and in vivo for its ability to suppress juvenile hormone (JH) biosynthesis by corpora allata of Locusta migratoria migratorioides. Fluvastatin inhibited JH biosynthesis by corpora allata in vitro. Exogenous mevalonic acid lactone restored JH biosynthesis in corpora allata inhibited by fluvastatin. Fluvastatin injected into locusts in vivo inhibited JH biosynthesis, but maximal inhibition lasted for only 6 hr. There were no discernible effects on either JH-regulated metamorphosis or oocyte maturation. Lengthening of the fourth larval stadium was observed and increased doses (single or repeated injections) were fatal.

Carcinogenicity and Mutagenicity Studies with Fluvastatin, a New, Entirely Synthetic HMG-CoA Reductase Inhibitor

The HMG-CoA reductase inhibitors are a new and novel class of cholesterol-lowering agents which are widely used worldwide. Fluvastatin is the first entirely synthetic compound in this class and is structurally distinct from fungal metabolite derivatives which are already marketed. As the liver is the site of some toxic effects for these compounds, it was not entirely unexpected that liver cancer was found in rats and/or mice with the first three marketed compounds, lovastatin, pravastatin, and simvastatin. Four lifetime carcinogenicity studies (two rat and two mouse) did not give any evidence that fluvastatin induced liver tumors in rodents. Fluvastatin induced thyroid neoplasms in rats and forestomach papillomas in rodents, as other compounds in this pharmacologic class have also done. The genotoxic potential of fluvastatin has been assessed in vitro using Salmonella typhimurium, Escherichia coli (gene mutations), V79 Chinese hamster cells (HGPRT gene mutations, chromosomal aberrations), rat hepatocyte primary cultures (DNA repair), and BALB/3T3 cells (malignant transformations). Fluvastatin was also tested in vivo for clastogenicity using the mouse bone marrow micronucleus test and by performing a cytogenetic analysis in the rat bone marrow after acute and subacute treatment. In all seven assays fluvastatin was found to be free of any genotoxic potential.

Alteration of egg yolk cholesterol content and plasma lipoprotein profiles following administration of a totally synthetic HMG-CoA reductase inhibitor to laying hens

PD 123244-15 [(±)-(R * ,R * )-3,4-dibromo-β,δ-dihydroxy-2-(4-fluorophenyl)-5-(1-methylethyl)-1H- pyrrol-1-heptanoic acid, sodium salt], a totally synthetic HMG-CoA reductase inhibitor, was fed to laying hens at dietary levels of either 0, 0.009, 0.027, or 0.082% for 20 days (experiment 1) or 0, 0.027, 0.055, or 0.082% for 42 days (experiment 2). In each experiment, PD 123244-15 generally had little effect on egg or yolk weights, while hens fed 0.082% PD 123244-15 produced fewer eggs than the other three groups

RG 12561 (dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent.

RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 mumol/l, respectively. In a rat ex vivo assay, orally administered RG 12561, lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91%, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16%, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent.

Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase

CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly liver-selective using an ex vivo approach. In order to determine liver-selectivity at the cellular level, CI-981 was evaluated in cell culture and compared to lovastatin, pravastatin, fluvastatin and BMY-21950. Using human cell lines, none of the compounds tested showed liver-selectivity, i.e. strong inhibition of cholesterol synthesis in Hep-G2 cells (liver model) but weak inhibition in human fibroblasts (peripheral cell model). In contrast, all drugs tested produced equal and potent inhibition of sterol synthesis in primary cultures of rat hepatocytes, and CI-981, pravastatin and BMY-21950 were more than 100-fold more potent in rat hepatocytes compared to human fibroblasts. Since all compounds were also equally potent at inhibiting sterol synthesis in a rat subcellular system and in vivo, the data suggest that the use of Hep-G2 cells may not be the cell system of choice in which to study inhibition of hepatic cholesterogenesis or to demonstrate liver selectivity of inhibitors of HMG-CoA reductase.

A potent, tissue-selective, synthetic inhibitor of HMG-CoA reductase.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA potent, tissue-selective, synthetic inhibitor of HMG-CoA reductaseN. Balasubramanian, P. J. Brown, J. D. Catt, W. T. Han, R. A. Parker, S. Y. Sit, and J. J. WrightCite this: J. Med. Chem. 1989, 32, 9, 2038–2041Publication Date (Print):September 1, 1989Publication History Published online1 May 2002Published inissue 1 September 1989https://doi.org/10.1021/jm00129a004RIGHTS & PERMISSIONSArticle Views481Altmetric-Citations26LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (427 KB) Get e-Alerts Get e-Alerts

Utilization of the chiral synthon, methyl 3-O-benzyl-2,4,6-trideoxy-6-iodo-α-D- [formula omitted]-hexopyranoside in the synthesis of a potent HMG-CoA reductase inhibitor

Compound 1, a potent synthetic HMG-CoA reductase inhibitor, has been synthesized from the chiral synthon, methyl 3-O-benzyl-2,4,6-trideoxy-6-iodo-α-D- erythro -hexopyranoside ( 2), utilizing a novel palladium-mediated procedure for benzyl ether cleavage.