ABSTRACT
The electronic absorption, fluorescence excitation and emission spectra, and fluorescence quantum yields of novel fused thienobenzofurans, including thieno[3,2-b][1]benzofuran (1), [1]benzothieno[3,2-b]furan (2), and [1]benzothieno[3,2-b][1]benzofuran (3), were recorded in fourteen solvents of different polarities at room temperature. Compound 2 was not fluorescent. Experimental ground-state dipole moments of compounds 1-3 were measured in benzene at 298 K and compared with the corresponding theoretical dipole moment values. The solvent effects on the electronic absorption and fluorescence spectra of these thienobenzofurans were quantitatively investigated by means of solvatochromic correlations based on the Kawski-Chamma-Viallet and McRae equations. A weak negative solvatochromic behavior was found for these compounds, showing that their dipole moments are slightly lower in the excited singlet-state than in the ground-state. Kamlet-Abboud-Taft multiparameter relationships were also established for electronic absorption and fluorescence wavenumbers, and fluorescence quantum yields in most solvents, demonstrating the occurrence of specific solute-solvent interactions.
Subject(s)
Benzofurans/chemistry , Fluorescence , Quantum Theory , Molecular Structure , Solvents/chemistry , Spectrometry, Fluorescence , Spectrophotometry, UltravioletABSTRACT
Structure based ligand design was used in order to design a partial agonist for the PPARdelta receptor. The maximum activation in the transactivation assay was reduced from 87% to 39%. The crystal structure of the ligand binding domain of the PPARdelta receptor in complex with compound 2 was determined in order to understand the structural changes which gave rise to the decrease in maximum activation.
Subject(s)
Butyrates/chemistry , Butyrates/pharmacology , PPAR delta/agonists , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Drug Design , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARdelta activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPARdelta potency of 0.13 microM, which is 50-fold more potent than compound 5.
Subject(s)
PPAR delta/agonists , Models, Molecular , Molecular StructureABSTRACT
The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.
Subject(s)
Allyl Compounds/chemical synthesis , Lipid Metabolism/drug effects , PPAR delta/agonists , Phenylacetates/chemical synthesis , Administration, Oral , Allyl Compounds/pharmacokinetics , Allyl Compounds/pharmacology , Animals , Apolipoprotein B-100/genetics , Binding Sites , Cell Line , Cholesterol Ester Transfer Proteins/genetics , Crystallography, X-Ray , Dietary Fats/administration & dosage , Fatty Acids, Nonesterified/metabolism , Female , Humans , Male , Mice , Mice, Transgenic , Models, Molecular , Muscle, Skeletal/cytology , Oxidation-Reduction , Phenylacetates/pharmacokinetics , Phenylacetates/pharmacology , Rats , Structure-Activity Relationship , Transcriptional ActivationABSTRACT
Computational analysis of the ligand binding pocket of the three PPAR receptor subtypes was utilized in the design of potent PPARalpha agonists. Optimum PPARalpha potency and selectivity were obtained with substituents having van der Waals volume around 260. Compound 6 had a PPARalpha potency of 0.002 microM and a selectivity ratio to PPARgamma and PPARdelta of 410 and 2000, respectively.