Five new series of potential hypolipidemic agents 3-7 were synthesized, in order to establish the minimal pharmacophore features associated to the potent hypocholesterolemic activity of natural a-asarone (1) and synthetic clofibrate mimetic derivatives 2. The compounds were examined in hyperlipidemic male mice after oral administration of 25, 50, and 100 mg/Kg for 6 days. The isomeric series of acids and esters 3a-3c and 4a-4c were unexpectedly less active than the most simple structural isomeric compounds 5-7. This reveals that the phenoxyacetic acid scaffold carrying a hydrocarbon side chain, also found in derivatives 2, seems to be the most favorable lead for further development of potent hypolipidemic drugs. Drug Dev.
A series of bioisosteric analogues of fibrates, such as clofibrate (2) and bezafibrate (3), was designed, considering the pharmacophore potential of phenoxyacetic derivatives 4 related to a-asarone (1) in their structure. Thus, the hypolipidemic activity of the series of amides 5a-5j, 6a-6d, and 7a-7c, amines 8b-8d, and amino acids 9a-9e has been evaluated. A significant decrease in serum cholesterol was observed in mice for a number of these compounds. Some of them also showed a lowering of low-density lipoprotein cholesterol, and a few had an effect on increasing the high-density lipoprotein cholesterol levels, and on reducing the triglyceride serum contents. Phenoxyacetic, phenoxyethyl-amido and -amino moieties, as well as the presence of a chlorine atom in their aromatic rings, were identified as potential pharmacophores. Unexpectedly, derivatives 9a-9e, bearing an amino acid group, did not exhibit any hypolipidemic activity under a similar pharmacological protocol. Drug Dev.
We study correlations in time series of RR intervals of subjects with normal sinus rhythm (NSR) during sleep and wake phases and we also analyze time series of subjects with congestive heart failure (CHF) in both phases. We use detrended fluctuation analysis (DFA), the Higuchi's method and multifractal analysis. We have obtained different results for sleep and wake phases. The time series of healthy subjects show long-range correlations during sleep and wake conditions; on the other hand, for CHF subjects we have found different correlations during sleep and wake phases. This is confirmed by using both DFA and Higuchi's methods. We have found that the width of the multifractal spectra is practically the same for both phases of healthy subjects and CHF subjects. However, when we study with detail the spectra we observe that the spectra of unhealthy persons are almost symmetrical whereas the spectra of healthy subjects are asymmetrical.
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