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High Lipophilicity (high + lipophilicity)
Selected AbstractsInfluence of lipophilicity and stereochemistry at the C7 position on the cardioprotective and antioxidant effect of ginkgolides during rat heart ischemia and reperfusion,DRUG DEVELOPMENT RESEARCH, Issue 3 2005Ludovic Billottet Abstract The extent to which the cardioprotective effect of ginkgolides is related to their lipophilicity rather than to their anti-platelet activating factor (PAF) effect was addressed in isolated rat hearts submitted to ischemia and reperfusion. A new derivative of ginkgolide C (1), the 7-,- O -(4-methylphenyl) ginkgolide C (4) was synthesized and compared to 7- O -(4-methylphenyl) ginkgolide C (2) that had the same absolute configuration at C7 as 1 for its lipophilicity, anti-PAF activity, and cardioprotective and antioxidant effects. Using reversed-phase high-performance liquid chromatography HPLC, 4 and 2 were found to be significantly more lipophilic (i.e., log kw of 3.42±0.05 and 3.64±0.07, respectively) than 1 (1.15±0.03) and the strong PAF inhibitor ginkgolide B (GkB; 1.65±0.03). The anti-PAF activities (IC50 values in ,M) were 8.2, 17.1, and 2.2 for 4, 1, and GkB, respectively, while 2 was inactive. In preischemic and/or reperfused hearts perfused with ginkgolides at 0.7 ,M: (i) 2 and 4 were more efficient in improving postischemic hemodynamic and metabolic recovery than 1, (ii) a key-step in cardioprotection occurred during ischemia where 2 and 4 limited myocardial ATP depletion and contracture development, (iii) a strong anti-lipoperoxidant effect was observed with 2 and 4, but not 1. In vivo administration of 2 to rats (4 mg/kg/day for 20 days) was more effective than that of 1 regarding ischemic heart protection, suggesting a positive role for lipophilicity. It was concluded that a high lipophilicity is not an absolute prerequisite for a strong anti-PAF effect for ginkgolides, whereas it appears essential for cardioprotection. Drug Dev. Res. 64:157,171, 2005. © 2005 Wiley-Liss, Inc. [source] Pharmacokinetics and metabolism of the novel synthetic C -nucleoside, 1-(2-deoxy- , -D-ribofuranosyl)-2,4-difluoro- 5-iodobenzene: a potential mimic of 5-iodo-2,-deoxyuridineBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2002Panteha Khalili Abstract 1-(2-Deoxy- , -D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR) is one of the several unnatural 1-(2-deoxy- , -D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes recently synthesized for evaluation as anticancer, antiviral and diagnostic imaging agents. This class of C -nucleosides was designed to exploit several potential advantages relative to classical 5-substituted-2,-deoxyuridines, including stability towards phosphorolysis by pyrimidine phosphorylase, increased lipophilicity that may alter their ability to cross the blood,brain-barrier, and a greater resistance towards catabolism and deiodination. The physiochemical evaluation of 5-IDFPdR showed high lipophilicity (log P=2.8), moderately high protein binding (70,75%), stability towards phosphorolysis (e.g. no evidence of metabolic deglycosylation) by thymidine phosphorylase, and minimal microsomal metabolism in vitro. Pharmacokinetic studies of 5-IDFPdR in rat were characterized by a short elimination half-life (9,12 min), modest urinary elimination in pooled 0,24 h urine specimens (10,14%, including 2% as unconjugated drug) and high oral bioavailability (F=0.96). Both glucuronide and sulfate metabolites were present in urine. Glucuronidation was the predominant conjugation pathway. Copyright © 2002 John Wiley & Sons, Ltd. [source] Distinct effects of atypical 1,4-dihydropyridines on 1-methyl-4-phenylpyridinium-induced toxicityCELL BIOCHEMISTRY AND FUNCTION, Issue 1 2007Linda Klimaviciusa Abstract Our previous data obtained from in vivo experiments demonstrated high neuroprotective effects of three novel atypical neuronal non-calcium antagonistic 1,4-dihydropyridine (DHP) derivatives cerebrocrast, glutapyrone and tauropyrone. The present studies were carried out in vitro to clarify, at least in part, their mechanism of action in primary culture of cerebellar granule cells by use of 1-methyl-4-phenylpyridinium (MPP+) as a neurotoxic agent which causes dramatic oxidative stress. Cerebrocrast (highly lipophilic, with a classical two-ring structure) dose-dependently (0.01,10.0,µM, EC50,=,13,nM) reduced MPP+ -induced cell death. At the same time, the calcium antagonist nimodipine (reference drug) protected cell death at much higher concentrations (EC50,=,12.4,µM). Cerebrocrast decreased also the generation of reactive oxygen species and loss of mitochondrial membrane potential. In contrast, low lipophilic amino acid-containing DHPs glutapyrone and tauropyrone (glutamate- and taurine-containing, correspondingly) were without significant effects indicating their distinct mode of action in comparison to cerebrocrast. We have demonstrated for the first time an ability of atypical non-calcium antagonistic DHP cerebrocrast (which has classical DHP structure elements and high lipophilicity) to protect MPP+ -induced deterioration of mitochondrial bioenergetics. One may suggest mitochondria as an essential intracellular target for the neuroprotective action of cerebrocrast and indicate its usefulness in the treatment of Parkinson's disease. Copyright © 2006 John Wiley & Sons, Ltd. [source] Effect of new and known 1,4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic ratsCELL BIOCHEMISTRY AND FUNCTION, Issue 4 2004na Briede Abstract Analysis of the effect of several 1,4-DHP Ca2+ channel antagonists on experimental and clinical diabetes shows that structurally similar Ca2+ channel antagonists can exert opposite effects on Ca2+ influx, glucose homeostasis and insulin secretion. The influence of the Ca2+ channel antagonists on pancreatic , cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNAREs protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ-induced diabetic rats. The compounds tested were: 1,4-DHP derivatives cerebrocrast (1), etaftoron (2), OSI-1190 (3), OSI-3802 (4), OSI-2954 (5) and known 1,4-DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure,function relationships of the effect of 1,4-DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF2 group in position 2 of the 4-phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5,mg,kg,1, p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ-induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long-lasting influence on glucose metabolism, especially in STZ-induced diabetic rats. Copyright © 2004 John Wiley & Sons, Ltd. [source] | ||||||||||