Potent HMG-CoA Reductase Inhibitor Research Articles

Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase. (2). Absorption, Distribution, Metabolism, Excretion and Accumulation Following Repeated Oral Administration of 14C-NK-104 in Rats.

NK-104 is a very potent competitive inhibitor of HMG-CoA reductase. In this study, the absorption, distribution, excretion and metabolism of 14C NK-104 were investigated during and after repeated oral administration to male rats at a daily dose of 1 mg/kg for nine days. The levels of radioactivity in the plasma at 0.5 and 24 hr after daily dosing reached a steady state after the 4th administration, and levels were about 2 times higher than those after the 1st administration. High levels of radioactivity were detected in the liver during the repeated administration with maximum levels being 35-51 times higher than those in plasma. The level of radioactivity in other tissues after final administration was about 3 times that after the 1st administration. The elimination of radioactivity from the tissues was rapid and complete by 144 hr after the final administration. The excretion ratio of radioactivity in the urine and feces up to 144 hr after the 9th administration was 0.14 and 97.91%, respectively. Unchanged NK-104 was mainly found in plasma during the repeated oral administration. Two major metabolites, M-6 (pentenoic acid derivative) and M-8 (propenoic acid derivative), as β-oxidation products of NK-104, were found in heart and skeletal muscle after the repeated oral administration at levels 2-4 times than after single administration. The radioactivity present in feces predominantly considered of the unchanged drug during the repeated administration. In conclusion, there was no significant accumulation of radioactivity due to repeated administration of 14C-NK-104 to rats.

Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase. (3). Foeto-placental Transfer and Mammary Excretion after Oral Administration in Rats.

NK-104 is a very potent competitive inhibitor of HMG-CoA reductase. In this study, the transfer of radioactivity into the fetus and milk were investigated in pregnant and lactating rats after a single oral administration of 14C-NK-104 at a dose of 1 mg/kg. Whole body autoradiograms of rats on the 18th day of gestation showed a low distribution of radioactivity to amniotic fluid and fetus. On the 13th and 18th day of gestation, the levels of radioactivity in the placenta tissue were less than those in the maternal plasma. Therefore little radioactivity was transferred into the fetus, accounting for less than 36% of that in maternal plasma. The radioactivity in the milk reached a maximum level at 6 hr after administration to the lactating rats on the 14th day after delivery, being seven times higher than that in the maternal plasma. Although the composition of radioactivity in the milk consisted mostly of the unchanged NK-104, its concentration was below the detection limit at 48 hr.

2.P.59 Efficacy and safety of cerivastatin, a novel potent HMG-CoA reductase inhibitor, in primary hypercholesterolaemia: A comparative study

2.P.59 Efficacy and safety of cerivastatin, a novel potent HMG-CoA reductase inhibitor, in primary hypercholesterolaemia: A comparative study

2.P.71 NK-104, a potent HMGCoA-reductase inhibitor, increases intracellular degradation of apo B-100 and decreases its secretion in HepG2 cells

2.P.71 NK-104, a potent HMGCoA-reductase inhibitor, increases intracellular degradation of apo B-100 and decreases its secretion in HepG2 cells

3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors Unmask Cryptic Regulatory Mechanisms

The possibility that potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may alter the mechanisms by which dietary cholesterol and farnesol regulate this gene was investigated by comparing the regulatory responses of rats maintained on diets with or without 0.04% Lovastatin supplementation to dietary cholesterol. It was found that the rate of hepatic HMG-CoA reductase transcription was significantly decreased by dietary cholesterol in animals fed Lovastatin-supplemented diets, whereas animals maintained on a normal chow diet showed no decrease in the rate of transcription. The levels of reductase mRNA were decreased to about 10% of controls in Lovastatin-supplemented animals in response to dietary cholesterol but not affected in nonsupplemented animals. Administration of farnesol, reputed to be the nonsterol regulator of reductase, to rats maintained on a diet containing Lovastatin decreased hepatic HMG-CoA reductase protein by 30% and the half-life of reductase immunoreactive protein to 4.0 h, which is close to that observed in chow-fed animals. In contrast, farnesol treatment does not affect the turnover rate of reductase protein in rats fed a normal chow diet. These results suggest that potent inhibitors of HMG-CoA reductase may unmask transcriptional regulation by dietary cholesterol and accelerated degradation of the reductase by the putative nonsterol regulator farnesol.

Cerivastatin, a New Potent Synthetic HMG Co-A Reductase Inhibitor: Effect of 0.2 mg Daily in Subjects With Primary Hypercholesterolemia.

BACKGROUND: Reduction of serum cholesterol, most notably low-density lipoprotein cholesterol is associated with reductions in cardiovascular morbidity and mortality. Statins have been shown to effectively reduce low-density lipoprotein cholesterol via inhibition of the hydroxymethyl-coenzyme A (HMG-CoA) reductase. Cerivastatin is the most potent HMG-CoA reductase inhibitor currently under study in the United States. METHODS AND RESULTS: A parallel group, randomized, placebo-controlled, double-blind, multicenter study was conducted to compare the efficacy and safety of three different dosing regimens of 0.2 mg/day of cerivastatin, a new HMG-CoA reductase inhibitor, in patients with hypercholesterolemia. After a 10-week diet-placebo lead-in period, 319 patients with low-density lipoprotein cholesterol >160 mg/dL were randomized to 4 weeks of treatment with one of the following regimens: cervastatin 0.1 mg twice daily, cerivastatin 0.2 mg once daily with the evening meal, cerivastatin 0.2 mg once daily at bedtime or placebo. All three active treatment groups produced statistically significant (P <.05) changes compared to aseline and placebo in total cholesterol (0.1 mg twice daily \_18.9%; 0.2 mg once daily with the evening meal: \_21.9%; 0.2 mg once daily at bedtime: \_22.1%; placebo: 0.0%), low-density lipoprotein cholesterol (0.1 mg twice daily: \_25.7%; 0.2 mg once daily with the evening meal: \_29.4%; 0.2 mg once daily at bedtime: \_30.4%; placebo: 1.4%) and high-density lipoprotein cholesterol (0.1 mg twice daily: 5.3%; 0.2 mg once daily with the evening meal: baseline and placebo, were also reduced by all active treatments (0.1 mg twice daily: \_11.6% [P =.05]; 0.2 mg once daily with the evening meal: \_11.6% [P =.05]; and 0.2 mg at bedtime: \_10.9% [P =.07]). The percentage change in total cholesterol and low-density lipoprotein cholesterol after 4 weeks of therapy for the once-daily cerivastatin groups was statistically significantly greater (P <.05) than the cerivastatin twice daily regimen. A treatment responser was seen by 1 week of therapy and was maximal by 3 weeks. The drug was well tolerated in all three dosing regimens and resulted in no significant increase in biochemical or clinical side effects compared to placebo. CONCLUSION: Cerivastatin is a novel, highly potent, well-tolerated HMG-CoA reductase inhibitor that produces low-density lipoprotein cholesterol reductions of approximately 30% when administered at 0.2 mg once a day in the evenings.

Biochemical and Molecular Approaches for Production of Pravastatin, a Potent Cholesterol-Lowering Drug

The intensive search for inhibitors of cholesterol biosynthesis by screening culture broths has spanned more than 20 years here at Sankyo. Resulting from our efforts, ML-236B was discovered in Japan as the first potent and specific inhibitor of HMG-CoA reductase. This compound contributed-to the Nobel Prize-winning work of Goldstein and Brown in which they elucidated the mechanisms of the LDL receptor pathway. After the discovery of ML-236B, many attempts were performed to find other HMG-CoA reductase inhibitors, and some potent inhibitors including pravastatin have already been launched. HMG-CoA reductase inhibitors are in worldwide clinical use and play a pivotal role in the therapy of hyperlipidemic patients. Pravastatin is produced by a two-step fermentation, firstly ML-236B is produced by Penicillium citrinum followed by the hydroxylation of ML-236B by S. carbophilus to form pravastatin. Recent advances in the molecular characterization of the Cyt P-450sca-2 and their responsiveness to ML-236B and PB in bacterial cultures should help elucidate the underlying cellular and molecular mechanisms of ML-236BNa and PB induction. In an effort to increase the productivity of this fermentation process, new technologies have been developed, and the mechanism of hydroxylation has been extensively investigated.

Synthesis of an Artificial HMG-CoA Reductase Inhibitor NK-104 via a Hydrosilylation–Cross-Coupling Reaction

Abstract The hydrosilylation of t-butyl (3R,5S)-3,5-isopropylidenedioxy-6-heptynoate with ClMe2SiH and a platinum catalyst, t-Bu3P·Pt(CH2=CHSiMe2)2O, gave an (E)-vinylsilane in high yield with high regioselectivity. A subsequent cross-coupling reaction with an aryl halide afforded t-butyl (3R,5S,6E)-7-aryl-3,5-isopropylidenedioxy-6-heptenoate. This sequence was applied to the synthesis of a potent HMG-CoA reductase inhibitor, NK-104.

P1-54 - Pharmacological studies on NK-104, a novel potent HMG-CoA reductase inhibitor (2): Plasma lipid-lowering effects in guinea pigs

P1-54 - Pharmacological studies on NK-104, a novel potent HMG-CoA reductase inhibitor (2): Plasma lipid-lowering effects in guinea pigs

P1-53 - Pharmacological studies on NK-104, a novel potent HMG-CoA reductase inhibitor (1): Inhibitory effects on the enzyme (in vitro) and sterol synthesis (in vivo) in rats and hypolipidemic effects in dogs

P1-53 - Pharmacological studies on NK-104, a novel potent HMG-CoA reductase inhibitor (1): Inhibitory effects on the enzyme (in vitro) and sterol synthesis (in vivo) in rats and hypolipidemic effects in dogs

Synthesis of Artificial HMG-CoA Reductase Inhibitors Based on the Olefination Strategy

Abstract Synthetic methods were studied for optically active 6-oxo-3,5-isopropylidenedioxyhexanoate esters (4), which could be used as a key precursor of various kinds of artificial analogs of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. An enantiomer (+)-4 was prepared by asymmetric reduction of β,δ-diketo esters derived from the Taber’s alcohol or l-tartrate followed by a series of chemical transformations, and the desired enantiomer (−)-4 was prepared by the same asymmetric reduction starting from d-tartrate. The key intermediate (−)-4 was finally converted into a highly potent HMG-CoA reductase inhibitor, NK-104.

A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross coupling sequence

The regioselective hydroboration of ethyl ( 3R, 5S)-3,5-isopropylidenedioxy-6-heptynoate, followed by the cross-coupling reaction with an aryl halide, provides ethyl ( 3R, 5S, 6E)-7-aryl-3,5-isopropylidenedioxy-6-heptenoate, a precursor of a highly potent HMG-CoA reductase inhibitor NK-104.

A new synthesis of HMG-CoA reductase inhibitor NK-104 through hydrosilylation-cross coupling reaction

Regioselective hydrosilylation of t-butyl (3 R,5 S)-3,5- syn-isopropylidenedioxy-6-heptynoate with ClMe 2SiH and a catalyst t-Bu 3P·Pt(CH 2=CHSiMe 2) 2O gives an ( E)-vinylsilane which undergoes cross coupling reaction with aryl halide to afford t-butyl (3 R,5 S,6 E)-7-aryl-3,5- syn-isopropylidenedioxy-6-heptenoate, a precursor of a highly potent HMG-CoA reductase inhibitor NK-104.

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.

Inhibitors of HMG-CoA reductase. Biological effects of A 6-[2-[2-(4-fluoro-3-methylphenyl)-4-substituted cyclohexe-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-one

We report on a series of potent inhibitors of HMG-CoA reductase (HMGR) that were designed to examine the biological consequences that result from molecular changes in RG 12561. The introduction of functional groups on the cyclohexene nucleus of RG 12561 and the resulting inhibitor-enzyme interactions at remote binding sites of HMGR are discussed. Cellular membrane permeability may also contribute to potency. The HMGR inhibitory activity was measured utilizing solubilized enzyme. The compounds were evaluated as inhibitors of sterol biosynthesis in vitro using liver slices and in vivo after oral administration to the rat.

The effect of 25-hydroxycholesterol on the regulation of apolipoprotein E mRNA levels and secretion in the human hepatoma HepG2

The human hepatoma cell line, HepG2, was cultured with 25 OH cholesterol, a potent inhibitor of HMG-CoA reductase, in order to examine the effect of the oxysterol on apo E synthesis and secretion. Treatment of cells with oxysterol (2.5 μM) resulted in a greater than 90% inhibition of HMG-CoA reductase activity and a 3-fold reduction in its cognate mRNA level. However, apo E mRNA level and secretion were not affected after 24 h of drug treatment. This drug treatment was associated with a reduction in both cellular free and esterified cholesterol levels by 50% and 40%, respectively. Exposure of HepG2 cells to an ACAT inhibitor, the Sandoz compound (58-035) for 24 h, at a concentration of 5 μg/ml, resulted in a 30% increase and 70% decrease in the intracellular levels of free and esterified cholesterol, respectively. Under this regimen of drug treatment, the level of apo E mRNA was increased by approximately 70%, while HMG-CoA reductase mRNA level was decreased by 35%. When the cells were exposed to the combination of the ACAT inhibitor and 25 OH cholesterol, the cellular levels of free and esterified cholesterol were reduced by 30% and 80%, respectively. This combination of drugs had no effect on apo E mRNA; however, the level of HMG-CoA reductase mRNA was decreased by 3.5-fold. Taken together, the data suggested that reduction in the intracellular levels of either free or esterified cholesterol had no effect on apo E mRNA level. By contrast, a small increment in cellular free cholesterol content was associated with a significant induction in apo E mRNA level. Furthermore, 25 OH cholesterol caused a significant redistribution (50%) of apo E from the HDL fraction to the d > 1.21 g/ml infranatant. By using high performance liquid chromatography and molecular sieve columns, it was found that the appearance of a lipid-poor apo E particle was not an artifact of ultracentrifugation. This particle contained 85 wt% protein and 15 wt% of free cholesterol and phospholipid. The results suggested that a lipid-poor apo E particle was secreted by the HepG2 cells under certain circumstances.

The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase

Three alternative methods for the synthesis of the optically active heptanoate ( 6), a key intermediate in the preparation of a highly potent and tissue selective HMG Co-A reductase inhibitor are described.

A novel enantioselective synthesis of HMG Co-A reductase inhibitor NK-104 and a related compound

Optically active methyl 6-oxo-3,5- syn-isopropylidenedioxyhexanoate ( 5) was prepared by enantioselective syn-reduction of β,δ-diketo ester 2, followed by hydrolysis, protection of the diol moiety and ozonolysis, and was converted into a highly potent HMG Co-A reductase inhibitor NK-104 and an analogue.

Effect of Pravastation on Serum Lipids, Apolipoproteins and Lipoprotein (a) in Patients with Non-Insulin Dependent Diaabetes Mellitus.

In 43 patients with non-insulin dependent diabetes mellitus (NIDDM) associated with hypercholesterolemia, the effect of pravastatin, a potent HMG CoA-reductase inhibitor, on serum lipids, apolipoproteins and lipoprotein (a) was examined. After 1 to 3 months administration of 10 mg per day of pravastatin, the serum levels of total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) were significantly decreased, while the serum level of high density lipoprotein cholesterol (HDL-C) was significantly increased in patients with NIDDM. The levels of apolipoproteins B (apo B) and E were significantly decreased, while apolipoprotein AI (apo A-I) was not changed by the administration of pravastatin. The atherogenic indices (LDL-C/HDL-C and apo B/apo A-I) were significantly decreased by the administration of this drug. The serum lipoprotein (a), which was increased in the diabetic patients, was not affected by the pravastatin treatment. Plasma glucose and hemoglobin A1c levels were not affected by the treatment. We concluded that pravastatin is a potentially useful agent in the treatment of hypercholesterolemia in patients with NIDDM.

O-253 - Effects of new potent HMG-CoA reductase inhibitors on smooth muscle cell proliferation and adhesion

O-253 - Effects of new potent HMG-CoA reductase inhibitors on smooth muscle cell proliferation and adhesion