Synthesis of 2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl] derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (8-12) is described. The chlorides used in the above synthesis can exist in two isomeric forms: chain (18-20) and cyclic (19a, 20a). The compounds 8-12 exhibited potent analgesic activity which was superior than that of acetylsalicylic acid in two different tests. Most of the investigated imides suppressed significantly spontaneous locomotor activity in mice.
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http://dx.doi.org/10.1016/s0014-827x(02)01302-2 | DOI Listing |
Toxicol Sci
January 2025
Takeda Development Center Americas, Inc, Cambridge, MA, USA.
The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding.
View Article and Find Full Text PDFGeroscience
January 2025
Center for Aging and Population Health, School of Public Health, University of Pittsburgh, 310 BelPB, 130 N. Bellefield Avenue, Pittsburgh, PA, 15213, USA.
Unintentional weight loss in older populations is linked to greater mortality and morbidity risks. This study aims to understand the metabolic mechanisms of unintentional weight loss and their relationship with body composition changes in older adults. We investigated plasma metabolite associations with weight and body composition changes over 5 years in 1335 participants (mean age 73.
View Article and Find Full Text PDFNeurochem Res
January 2025
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Brain accumulation of the branched-chain α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) occurs in maple syrup urine disease (MSUD), an inherited intoxicating metabolic disorder caused by defects of the branched-chain α-keto acid dehydrogenase complex. Patients commonly suffer life-threatening acute encephalopathy in the newborn period and develop chronic neurological sequelae of still undefined pathogenesis. Therefore, this work investigated the in vitro influence of pathological concentrations of KIC (5 mM), KMV (1 mM), and KIV (1 mM) on mitochondrial bioenergetics in the cerebral cortex of neonate (one-day-old) rats.
View Article and Find Full Text PDFJ Bone Miner Metab
January 2025
Universiti Kebangsaan Malaysia Health Science, UKM, 43600, Bandar Baru Bangi, Selangor, Malaysia.
Introduction: Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by an imbalance in chondrocyte metabolism. Ferroptosis has been implicated in the pathogenesis of OA. The role of Sirt1, a deacetylase, in mediating deacetylation during ferroptosis in OA chondrocytes remains underexplored.
View Article and Find Full Text PDFPlant Cell Physiol
December 2024
RIKEN Center for Sustainable Resource Science, Yokohama 230-0045, Japan.
Soybean (Glycine max) is a leguminous crop cultivated worldwide that accumulates high levels of isoflavones. Although previous research has often focused on increasing the soybean isoflavone content because of the estrogen-like activity of dietary soy in humans, the rapidly increasing demand for soybean as a plant-based meat substitute has raised concerns about excessive isoflavone intake. Therefore, the production of isoflavone-free soybean has been anticipated.
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