Delf Schmidt

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.

Untersuchungen zur struktur des α-d-glucosidaseinhibitors acarbose

Abstract Hydrolysis of the pseudotetrasaccharide acarbose ( 1 ), a potent inhibitor of intestinal α- d -glucosidases and an effective oral antidiabetic agent, gave d -glucose and a tricyclic compound (1 R ,2 S ,3 R ,4a S ,7 R ,8 S ,8a S ,9a R )-1,2,3,4a,7,8,8a,9a-octahydro-1,2,7,8-tetrahydroxy-3- [(1 R )-1-hydroxyethyl]-6-hydroxymethylpyrrolo-[2,1- b ]benzoxazole ( 6 ) that was further degraded into 1 l -(1,2,4/3)-1-hydroxymethyl-2,3,4-cyclohexanetriol (validatol, 25 ) and (2 R ,3 S ,4 S )-2-[(1 R )-1-hydroxyethyl]-pyrrolidine-3,4-diol ( 49 ) by sodium borohydride reduction and subsequent catalytic hydrogenation. Methanolysis of 1 afforded α- and β-glycosides 11 and 10 which were cleaved by hydrogenation to give 25 and methyl α- and β-glycosides of 4-amino-4,6-dideoxy-α- and β- d -glucopyranose (viosamine, 38 ). Upon hydrogenation, 1 gave, beside several minor products, 25 and a basic trisaccharide that was acetolyzed into the peracetates of viosamine 38 and d -glucose. The structure of 6 was determined by derivatives and ring-cleavage products. N.m.r. and mass spectra of the acarbose products and derivatives are discussed.

Preclinical review of cerivastatin sodium—a step forward in HMG-CoA reductase inhibition

Epidemiological studies have established that elevated concentrations of plasma cholesterol, particularly the low density lipoprotein (LDL) cholesterol, is one of the major risk factors for the development of arteriosclerosis and ischemic heart disease. Treatment with HMG-CoA reductase inhibitors (vastatins) has become the most successful drug treatment in lowering total plasma and LDL cholesterol concentrations in the last years. The vastatins already available for treatment are therapeutically used in a dose-range between 10 and 80 mg/day. The new enantiomerically pure pyridine derivative cerivastatin sodium has demonstrated its efficacy in significantly lower doses in the microgram-range, not only in preclinical but also in clinical studies with daily doses of only 0.1-0.3 mg. The differences in the therapeutic doses are reflected by the Ki- and IC50-values from enzyme inhibition tests in comparison with various HMG-CoA reductase inhibitors. Cerivastatin sodium exhibits much higher enzyme affinity with factors between 70 and almost 200. The Ki-value for cerivastatin sodium was 1.3 x 10(-9) M in comparison to 150 x 10(-9) M for lovastatin. The extremely high enzyme affinity of cerivastatin sodium was also reflected in its high activity in vivo. In acute in vivo studies cerivastatin sodium inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate in both rats and dogs by 50% after oral administration at doses of 0.002 mg/kg body weight (ED50-values). This dose was comparable to 0.3 mg/kg of lovastatin. In subchronic dog studies a dose of 0.03 mg/kg lowered the serum LDL cholesterol concentration by 35% which is comparable with doses of 8-10 mg lovastatin/kg. Interesting results were observed in cholestyramine-primed dogs when 0.1 mg cerivastatin sodium/kg p.o. markedly decreased the serum triglycerides up to 70%. Cerivastatin shows a favourable pharmacokinetic profile with high liver selectivity. Rat studies have shown almost complete absorption and rapid hepatic clearance. Cerivastatin was highly bound to plasma proteins of rats, dogs and humans (>98%). Cerivastatin metabolites were excreted mainly via feces. The metabolism of cerivastatin sodium in man follows two metabolic pathways, demethylation to metabolite M1 and stereospecific hydroxylation to M23. The three major metabolites M1, M23 and the hydroxylated and demethylated metabolite M24 are highly active inhibitors not only in vitro but also in vivo. The human specific metabolites M23 and M24 inhibited the HMG-CoA reductase isolated from rat liver with the same potency as the parent compound cerivastatin sodium (IC50: 1.0-1.2 x 10(-9) M). M1 was slightly less active. Corresponding pharmacological activity was observed in vivo. M23 and M24 inhibited [14C]cholesterol synthesis from [14C]acetate in rat liver with ED50)-values between 0.001 and 0.002 mg/kg body weight which is similar to cerivastatin sodium and M1 exhibited an ED50-value of <0.006 mg/kg The strong inhibitory activity of these metabolites, in addition to cerivastatins high enzyme affinity may explain the extraordinary pharmacological activity of cerivastatin and its ultra-low dose in man and demonstrates cerivastatin to be the most active HMG-CoA reductase inhibitor amongst all vastatins.

Remodelling of lipoproteins in transgenic mice expressing human cholesteryl ester transfer protein

Cholesteryl ester transfer protein (CETP) facilitates the transfer of reciprocal exchange of neutral lipids between lipoproteins. To better understand the function of CETP and its role in atherogenic pathways, transgenic mice which express human CETP were generated. The transgene encoding human CETP was under the control of the mouse alpha-fetoprotein enhancer and mouse albumin gene promoter and was expressed exclusively in the liver. The level of human CETP activity in transgenic mouse plasmas was found to be 1- to 5-fold greater than in normolipidemic human plasma. Human CETP induced an approx. 30 and 40% reduction of HDL cholesterol levels in plasma from female and male transgenic mice, respectively, when compared to controls. In addition, multiple alterations in mouse lipoprotein composition were observed in the transgenic mice. Diminished HDL cholesterol levels and disappearance of the apo E-rich HDL1 moiety account for the dramatic reduction in plasma cholesterol. The decrease in HDL cholesterol was accompanied by a marked reduction in HDL particle size and apo A-I content. The cholesterol content and the size of LDL particles increased, but only modestly, in transgenic mouse plasma. In conclusion, human CETP induces a significant remodelling of mouse lipoproteins which results in dramatic reduction in plasma cholesterol levels.

Biphenyls as Potent Vitronectin Receptor Antagonists. Part 2: Biphenylalanine Ureas

Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3).

Drug concentration monitoring, microbial alpha-glucosidase inhibitors, plasminogen activators

Drug Concentration Monitoring.- Microbial Alpha-Glucosidase Inhibitors: Chemistry, Biochemistry and Therapeutic Potential.- Plasminogen Activators: Molecular Properties, Biological Cell Function and Clinical Application.- Author Index Volumes 1-7.