Synthesis of polymeric thiazolidinedione and fibrate conjugates.

Pioglitazone is a thiazolidinedione (TZD) class of antidiabetic drug acting mainly through activation of PPARgamma which is a member of family of ligand activated nuclear hormone receptors. Clofibrate is an antilipemic drug acting through activation of PPARalpha. Despite the impressive antidiabetic activity of TZD, several side effects are implicated to use of this drug on some patient. Dual acting PPARalpha/gamma agonists have received increased attention to improve the profiles of the PPARgamma agonists. Hence, we describe here synthesis of TZD and/or fibrate derivatives-containing homo- or copolymers, poly(TZD) 7, poly(TZD-MAA) 8, poly(TZD-FA) 9, poly(FA) 10, and poly(FA-MAA) 11. The contents of TZD unit in copolymers, poly(TZD-MAA) 8 and poly (TZD-FA) 9 were 25 and 19 mol %, respectively. The number average molecular weights of the polymers determined by GPC were in range from 466 to 12600 and the polydispersity indices were in the range of 1.2-13.3.

Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells.

The blood-brain barrier contributes to maintain brain cholesterol metabolism and protects this uniquely balanced system from exchange with plasma lipoprotein cholesterol. Brain capillary endothelial cells, representing a physiological barrier to the central nervous system, express apolipoprotein A-I (apoA-I, the major high-density lipoprotein (HDL)-associated apolipoprotein), ATP-binding cassette transporter A1 (ABCA1), and scavenger receptor, class B, type I (SR-BI), proteins that promote cellular cholesterol mobilization. Liver X receptors (LXRs) and peroxisome-proliferator activated receptors (PPARs) are regulators of cholesterol transport, and activation of LXRs and PPARs has potential therapeutic implications for lipid-related neurodegenerative diseases. To clarify the functional impact of LXR/PPAR activation, sterol transport along the: (i) ABCA1/apoA-I and (ii) SR-BI/HDL pathway was investigated in primary, polarized brain capillary endothelial cells, an in vitro model of the blood-brain barrier. Activation of LXR (24(S)OH-cholesterol, TO901317), PPARalpha (bezafibrate, fenofibrate), and PPARgamma (troglitazone, pioglitazone) modulated expression of apoA-I, ABCA1, and SR-BI on mRNA and/or protein levels without compromising transendothelial electrical resistance or tight junction protein expression. LXR-agonists and troglitazone enhanced basolateral-to-apical cholesterol mobilization in the absence of exogenous sterol acceptors. Along with the induction of cell surface-located ABCA1, several agonists enhanced cholesterol mobilization in the presence of exogenous apoA-I, while efflux of 24(S)OH-cholesterol (the major brain cholesterol metabolite) in the presence of exogenous HDL remained unaffected. Summarizing, in cerebrovascular endothelial cells apoA-I, ABCA1, and SR-BI represent drug targets for LXR and PPAR-agonists to interfere with cholesterol homeostasis at the periphery of the central nervous system.

Synthesis, biological evaluation, and molecular modeling investigation of new chiral fibrates with PPARalpha and PPARgamma agonist activity.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyperlipidemia (fibrates) and insulin resistance (glitazones). Thus, there is significant interest in developing new and specific ligands for these receptors. Here, we present the results of the screening of new ligands of PPARalpha and PPARgamma. Optical isomers of new chiral fibrates were synthesized and tested in cell-based assays. Compound (S)-7 showed a dual PPARalpha/gamma activity, and its stereochemistry was crucial in receptor activation. Protease protection experiments suggested that this compound binds directly to PPAR. Moreover, computational studies showed that it properly docks to PPARalpha and gamma ligand binding pockets. Interestingly, (S)-7 exhibited only a modest capacity to induce the differentiation of murine fibroblasts 3T3-L1 into adipocytes compared to rosiglitazone, a well-known PPARgamma agonist.

Synthesis and antiplatelet activity of thioaryloxyacids analogues of clofibric acid.

The thiophene-, benzothiazole- and pyridine-thioaryloxyacids analogues of clofibric acid were synthesized and their antiplatelet activity was screened. Some compounds exhibited antiaggregating properties. The platelet-related haemostasis was measured on a PFA-100 analyzer using bull blood.

Isosteres of chiral clofibric acid analogs: synthesis, resolution, absolute configuration and HPLC detection of the optical purity.

Both racemic and enantiomeric forms of some isosteres of chiral clofibric acid analogs have been synthesized. Also, the absolute configuration has been established by chemical correlation and the optical purity determined by a simple HPLC procedure. Moreover, these studies show that the isosteric substitution of the ether oxygen atom of alpha-aryloxy-alkanoic acids with sulfur, amino and methylene groups lead to compounds in which both biological activity and stereoselectivity regarding chloride channel are highly reduced.

Synthesis, characterization, and preclinical evaluation of new thiazolidin-4-ones substituted with p-chlorophenoxy acetic acid and clofibric acid against insulin resistance and metabolic disorder.

We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

Synthesis and biological evaluation of 2-heteroarylthioalkanoic acid analogues of clofibric acid as peroxisome proliferator-activated receptor alpha agonists.

A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line.

[Synthesis and physico-chemical characterisation of some new derivatives of rutoside and clofibric acid]. / Sinteza si caracterizarea fizico-chimica a unor noi compusi ai rutozidului cu acidul clofibric.

Fibrates are drugs with efficacy in reducing blood cholesterol levels and especially, triglyceride plasma levels. Unfortunately, fibrates have a poor water-solubility and showed some adverse reactions at long treatment. The objective of this study was to obtain some new clofibric acid derivatives with rutin; some of these compounds contain a guanidine moiety, known as effective at cardiovascular level. All the compounds are soluble in water.

Synthesis and pharmacological evaluation of N'-morpholinomethylurea derivatives with platelet antiaggregant activity.

In the attempt to prolong and stabilize the known antiaggregant activity of morpholinomethylurea (MMU) derivatives were prepared with carboxylic acids possessing antiaggregant, anti-inflammatory or hypolipemic activity. The results of the experiments showed the important anti-aggregant and hypolipemic activity of N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104). The results obtained seem to indicate that the activity of these new N-acyl-N'-MMU is due initially to the molecule per se although it cannot be totally ruled out that part of the pharmacodynamic effect of the MMU may depend on a prodrug-like behaviour.