Anti-atherosclerosis effect of H2S donors based on nicotinic acid and chlorfibrate structures.

Based on the structures of nicotinic acid and chlorfibrate, a series of new H2S donors were synthesized and their anti-atherosclerosis activities using Ox-LDL RAW 264.6 cells as model were evaluated. The release test showed that all the compounds could release H2S effectively and showed low cytotoxicity. In the bioactivity experiments, compounds 1, 3, 9 and 14 increased the survival rate of HUVEC cells treated by ox-LDL; among four compounds, compounds 1 and 3 displayed higher activity than the others. In the foam cell model, compounds 1 and 3 were found to inhibit the formation of foam cells and significantly reduced the content of TC and FC in foam cells. They had more obvious effects on lipid reduction than those of nicotinic acid and chlorfibrate. In anti-oxidation, compounds 1 and 3 significantly reduced ROS and MDA and increased the expression level of SOD, whereas the precursor compounds, niacin and chlorfibrate had little antioxidant effect. In addition, both compounds also inhibited the inflammatory response in foam cells, with reducing pro-inflammatory factor TNF-α and increasing anti-inflammatory cytokine IL-10. WB assay showed that the tested compounds inhibited the expression levels PI3K, Akt and NF-κb proteins. In conclusion, the compounds as H2S donors could protect HUVEC cells from damage and inhibit the formation of foam cells by inhibiting PI3K/Akt/NF-κb signal pathway. All these suggest the compounds have potential to be candidate for anti-atherosclerosis medicines.

Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs.

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARα or PPARγ, while others were identified as dual agonists PPARα/γ.

Synthesis of highly water-soluble fibrate derivatives via BGLation.

Three water-soluble fibrates (fenofibrate, bezafibrate and chlofibrate) conjugated with a symmetrically branched glyceryl trimer (BGL003) were synthesized, and an evaluation of the fenofibrate-BGL003 conjugate as a candidate for anti-hyperlipemia drug was carried out using rats. The water-solubility of the fenofibrate-BGL003 conjugate was several thousand times greater than that of the original fenofibrate. The lipid-lowering effects of the fenofibrate-BGL003 conjugate were as strong as those of the same grams of fenofibrate. The actual active species of fenofibrate, fenofibric acid, was detected in rats' blood, but neither the fenofibrate-BGL003 conjugate nor fenofibrate was detected, probably due to enzymatic hydrolysis of the ester bond. The plasma concentration of fenofibric acid derived from the fenofibrate-BGL003 conjugate was five times higher than that derived from fenofibrate 4h after administration.

Synthesis and biological evaluation of new clofibrate analogues as potential PPARalpha agonists.

Clofibrate is a lipid-profile modifying agent belonging to the fibrate class of drugs. Fibrates are known to exhibit their beneficial effects by activating peroxisome proliferator-activated receptor-alpha (PPARalpha) and used in the treatment of dyslipidemia and atherosclerosis and for the prevention of heart failure. Hereby, the preparation of two new sets of clofibrate analogues, ethyl 2-(4-chlorophenoxy)-3-oxoalkanoates and ethyl 2-(4-chlorophenoxy)-3-hydroxyalkanoates is described starting from commercially available 3-oxoalkanoates in fair to good yields. Treatment of 3-oxoalkanoates with SO2Cl2 yielded the corresponding 2-chloro-3-oxoalkanoates, that were then converted into 2-(4-chlorophenoxy)-3-oxoalkanoates by reacting with sodium or caesium 4-chlorophenate. Reduction of the keto group with NaBH4 afforded the corresponding 2-(4-chlorophenoxy)-3-hydroxyalkanoates in very high yields and with variable diastereoselectivity. Biological evaluation of the compounds was performed by a transactivation assay in a transiently transfected monkey kidney fibroblast cell line. The newly synthesised clofibrate analogues failed to show noticeable levels of PPAR activation at concentrations where clofibrate showed an evident activity, suggesting that the structural modifications caused the loss of PPAR activity.

Synthesis and pharmacological evaluation of cis-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-ones. Tricyclic analogues related to the antilipidemic drug clofibrate.

The chemistry and pharmacology of two delta-lactones, cis-6-chloro-9a-methyl-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-one (2) and the 9a-demethyl analogue 3, are reported. Lactones were prepared from dihydrobenzofuran precursors possessing geometrical configurations confirmed both by synthesis and 1H NMR spectroscopy. All cis-dihydrobenzofurans exhibited Jvic = 9.0-10.8 Hz, whereas their trans isomers exhibited Jvic = 5.0--6.0 Hz in agreement with predictions based on the Karplus equation. The pharmacological profiles for 2 and 3 were compared to that of clofibrate (1) in normal male Sprague-Dawley rats. Using equimolar doses (0.4 mmol/kg, po, twice daily for 7 days), 1 exhibited both anticholesterolemic and antitriglyceridemic activity, lactone 2 exhibited only antitriglyceridemic activity, and 3 was inactive as an antilipidemic agent. No correlation was observed for inhibition of hepatic HMG-CoA reductase activity and serum cholesterol lowering.

Synthesis and antilipidemic properties of cis-7-chloro-3a, 8b-dihydro-3a-methylfuro[3,4-b]benzofuran-3(1H)-one, a tricyclic clofibrate related lactone having a structural resemblance to mevalonolactone.

The synthesis for the title lactone 2, designed to be an antagonist of the enzyme HMG-CoA reductase (E.C.1.1.1.34), is described. Lactone 2, its synthetic tricyclic hemiacetal precursor 4, and clofibrate were investigated for their antilipidemic activity in 7-day treated normal and in Triton WR-1339 induced hyperlipidemic male Sprague-Dawley rats. After 7-day drug administration to normal rats, lactone 2 was less effective than clofibrate in lowering HMG-CoA reductase activity and serum cholesterol; however, unlike clofibrate, lactone 2 did not increase liver weight or liver-body weight ratio or lower serum triglycerides. Since hemiacetal 4 selectively influenced triglycerides in normal animals, lactone 2 and hemiacetal 4 appear to have differential hypolipidemic effects. In the Triton hyperlipidemic model 2 and 4 lowered elevated triglycerides; only 4 significantly reduced elevated cholesterol levels; but neither 2 nor 4 was as effective as clofibrate. Differences in the observed antilipidemic properties for clofibrate, 2, and 4 in the two animal models are discussed. On the basis of preliminary biological data described in this article it is concluded that tricyclic analogues 2 and 4 represent reasonable leads for the development of new antilipidemic agents.

Synthesis and pharmacological evaluation of a clofibrate-related tricyclic spirolactone, 5-chloro-4',5-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2'-one.

The chemistry and pharmacology of the title compound, spirolactone 4, are reported. The synthesis represents a new approach to the preparation of spiro compounds. The pharmacological profiles of 4 are compared to that of clofibrate in Triton-induced hyperlipidemic, sucrose-fed, and normal Sprague-Dawley rat models. Clofibrate was effective in all animal models, but the spirolactone 4 exhibited antitriglyceridemic activity only in the Triton model. The inactivity of 4 in sucrose- and chow-fed rats could not be attributed to a resistance to hydrolysis by serum esterases. Comparative studies revealed that inhibition of hepatic HMG-CoA reductase activity may not be an index of hypocholesterolemic action in sucrose-fed rats. Additionally, only clofibrate exhibited significant changes in components of the hepatic microsomal monooxygenase system.

Amides of beta-(4-chlorophenoxy)-alpha-phenyl-ethylamines are inhibitors of cholesterol biosynthesis in vitro.

Amides of beta-(4-chlorophenoxy)-alpha-phenyl-ethylamines were prepared and tested for their inhibitory activity on cholesterol biosynthesis in vitro. Among the substances prepared, (II e), (II g), (II k) and (II m) had much greater inhibitory activity than clofibrate.

[Chemistry of phenoxyacetic acid esters of oxyalkyltheophyllines and 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methyl-propionate] (etofylline clofibrate), a novel antilipaemic agent (author's transl)]. / Zur Chemie der Phenoxyessigsäureester von Oxyalkyltheophyllinen und 1-(Theophyllin-7-yl)-äthyl-2-[2-(p-chlorphenoxy)-2-methylpropionat] (Etofyllinclofibrat), einem neuen Antilipämikum.

Esters of phenoxyacetic acids and oxyalkyltheophyllines were prepared as potential antihyperlipaemics. The basic idea was to ameliorate the known antilipaemic potency of phenoxyacetic acids and that of clofibric acid as the best known representative, respectively, by using alcoholic ester components with therapeutical efficacy of their own and to expand their therapeutical spectrum. Syntheses and preparative routes of these esters are presented. 1-(Theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methyl-propionate] (ML 1024; etofylline clofibrate; Duolip) was selected for further investigations. Characteristics and spectroscopic data of ML 1024 are described.

Azidofibrate. Synthesis and evaluation of its effects on fat cell lipolysis in vitro.

Synthesis and biological properties of a new ethyl alpha-(p-chlorophenoxy)-isobutyrate (clofibrate) analogue are described. Replacement of the chlorine atom of the parent drug by an azido group has been attempted in order to avoid the proliferative action on liver peroxysomes. The new compound showed a good degree of inhibition of rat fat cell lipolysis and its action, qualitatively different from that of clofibrate, bears some analogy with that of nicotinic acid.

Xanthone analogues of clofibrate / Synthesis and biological evaluation as antagonists of lipolysis in vitro.

By appropriate superimposing of fenofibrate and fenofibric acid molecules, two xanthone derivatives (closed models) may be obtained. These compounds as well as their four chlorine-free isomers were prepared and tested on adrenaline- and theophylline-induced lipolysis in rat fat cells in comparison with ethyl 2-(4-chlorophenoxy)-2-methylpropionate (clofibrate). Some of these new derivatives besides being good inhibitors of adrenaline effect, as clofibrate is, were also very active in reducing theophylline-induced lipolysis. Very promising for further studies is the chlorine-free 3-isomer (3e). The possible difference in the action mechanism of these compounds as compared with clofibrate and the structure-activity relationships are briefly discussed.

Hypolipemic activity of clofibrate-related compounds.

Ethyl-2(p-chlorophenoxy)-2-methylpropionate (clofibrate) related compounds were synthesized from substituted aryloxy acetic acids (III) either by esterification with selected alcohols (3,3,5-trimethylcyclohexanol and oxyalkyltheophyllines), by introduction into heterocyclic ring system (triazine type) or by amidation (aminotriazines and p-aminobenzoates). Lipid lowering effect was tested in normolipemic and hyperlipemic rats against clofibrate as reference. Some of these derivatives show high activity at low dosage, even under hyperlipemic conditions, whereas clofibrate is only slightly effective. From pharmacological results it can be suggested that the nature of acid group substituent is the main factor for efficacy, while the role of alpha-substituent is important for differentiation of activity against cholesterol and/or triglyceride.

Isonicotinates, nicotinates and clofibrates of N-methyl-N-(2-hydroxyethyl or 3-hydroxypropyl)--1,3,3-trimethylbicyclo [2.2.1]heptan-2-endo-amine with hypocholesterolemic and hypolipidemic activity.

The synthesis of isonicotinic, nicotinic and clofibric esters (III a, b, c) and (IV a, b, c) starting from N-methyl-N-(2-hydroxyethyl or 3-hydroxypropyl)-1,3,3-trimethylbicyclo [2.2.1] heptan-2-endo-amine is described. In general these esters showed a normolipemic activity in rats; in particular, the isonicotinic ester (IV a) showed a hypocholesterolemic activity higher than that of clofibric acid.