A series of [[(heterocyclyl)ethoxy]benzyl]-2,4-thiazolidinediones have been synthesized by the condensation of corresponding aldehyde 1 and 2,4-thiazolidinedione followed by hydrogenation. Both unsaturated thiazolidinedione 2 and its saturated counterpart 3 have shown antihyperglycemic activity. Many of these compounds have shown superior euglycemic and hypolipidemic activity compared to troglitazone (CS 045). The indole analogue DRF-2189 (3g) was found to be a very potent insulin sensitizer, comparable to BRL-49653 in genetically obese C57BL/6J-ob/ob and 57BL/KsJ-db/db mice. Pharmacokinetic and tissue distribution studies conducted on BRL-49653 and DRF-2189 (3g) indicate that these drugs are well-distributed in target tissues. On the basis of euglycemic activity as well as enhanced selectivity against reduction of triglycerides in plasma, DRF-2189 (3g) has been selected for further evaluation.
1. Metabolism of the antianxiety drug buspirone was studied by in vitro incubations with rat liver microsomes and hepatocytes. Metabolites were isolated and purified by h.p.l.c. The purified metabolites were identified by co-elution on h.p.l.c. with authentic standards and by g.l.c.-electron impact mass spectrometry of their trimethylsilyl (TMS) derivatives. 2. Five metabolites of buspirone were identified in the microsomal incubates and seven in the hepatocyte incubates. The major metabolites arose from aromatic hydroxylation at C-5, N-dealkylation of the butyl chain, and hydroxylation at C-6' and C-3' on the azaspirodecanedione moiety. 3. Metabolism of buspirone by rat liver microsomes was NADPH-dependent and was completely inhibited by cytochrome P-450 inhibitors SKF-525A and metyrapone. 4. Metabolites of buspirone formed in vitro were good predictors of the primary metabolites formed in vivo. 5. Hepatocytes and phenobarbital-induced rat liver microsomes were better predictors of in vivo metabolism of buspirone than non-induced rat liver microsomes. These in vitro systems should provide excellent models for studying the metabolism of other azaspirodecanedione-containing drugs.
A method is described for detection and quantitation of the major malondialdehyde-guanine adduct (M1G) based on thermospray liquid chromatography/mass spectrometry. A stable isotope analog of M1G ([2H2]M1G) was used as an internal standard. Thermospray mass spectra of M1G and [2H2]M1G showed intense protonated molecular (MH+) ions that were suitable for use in quantitation of M1G. M1G was purified from human urine and reduced with NaBH4 to a dihydro derivative that was cleanly separated from the contaminants in the urine. The detection limit of reduced M1G by thermospray liquid chromatography/mass spectrometry in the selected ion monitoring mode was 250 fmol on column. Six human urine samples were analyzed, and the concentrations of M1G were below the limit of detection of the assay (500 fmol/mL).
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