We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, ). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.9b01743 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Mitochondria as a Therapeutic Target: Focusing on Traumatic Brain Injury.
J Integr Neurosci
January 2025
Department of Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), 90050-170 Porto Alegre, Rio Grande do Sul (RS), Brazil.
Mitochondria are organelles of eukaryotic cells delimited by two membranes and cristae that consume oxygen to produce adenosine triphosphate (ATP), and are involved in the synthesis of vital metabolites, calcium homeostasis, and cell death mechanisms. Strikingly, normal mitochondria function as an integration center between multiple conditions that determine neural cell homeostasis, whereas lesions that lead to mitochondrial dysfunction can desynchronize cellular functions, thus contributing to the pathophysiology of traumatic brain injury (TBI). In addition, TBI leads to impaired coupling of the mitochondrial electron transport system with oxidative phosphorylation that provides most of the energy needed to maintain vital functions, ionic homeostasis, and membrane potentials.
View Article and Find Full Text PDFTrade-Off Between Enzymatic Antioxidant Defense and Accumulation of Organic Metabolite Affects Salt Tolerance of White Clover Associated with Redox, Water, and Metabolic Homeostases.
Plants (Basel)
January 2025
Department of Turf Science and Engineering, College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.
White clover () is an excellent perennial cold-season ground-cover plant for municipal landscaping and urban greening. It is, therefore, widely distributed and utilized throughout the world. However, poor salt tolerance greatly limits its promotion and application.
View Article and Find Full Text PDFHomocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease.
Int J Mol Sci
January 2025
Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632 Poznań, Poland.
Atherosclerosis is accompanied by inflammation that underlies cardiovascular disease (CVD) and its vascular manifestations, including acute stroke, myocardial infarction, and peripheral artery disease, the leading causes of morbidity/mortality worldwide. The monolayer of endothelial cells formed on the luminal surface of arteries and veins regulates vascular tone and permeability, which supports vascular homeostasis. Endothelial dysfunction, the first step in the development of atherosclerosis, is caused by mechanical and biochemical factors that disrupt vascular homeostasis and induce inflammation.
View Article and Find Full Text PDFBeneficial Effects of Reconstructed Human Gut Microbiota by Ginseng Extract Fermentation on Intestinal Cell Lines.
Microorganisms
January 2025
Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy.
Oxidative stress caused by reactive oxygen species (ROS) affects the aging process and increases the likelihood of several diseases. A new frontier in its prevention includes bioactive foods and natural extracts that can be introduced by the diet in combination with specific probiotics. Among the natural compounds that we can introduce by the diet, extract is one of the most utilized since it contains a vast number of bioactive molecules such as phenolic acids, flavonoids, and polysaccharides that have been shown to possess antioxidant, anti-ageing, anti-cancer, and immunomodulatory activity.
View Article and Find Full Text PDFA Cell-Based Evaluation of the Tyrosinase-Mediated Metabolic Activation of Leukoderma-Inducing Phenols, II: The Depletion of Augments the Cytotoxic Effect Evoked by Tyrosinase in Melanogenic Cells.
Biomolecules
January 2025
Division of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, Japan.
Chemical leukoderma is a disorder induced by chemicals such as rhododendrol and monobenzone. These compounds possess a -substituted phenol moiety and undergo oxidation into highly reactive and toxic -quinone metabolites by tyrosinase. This metabolic activation plays a critical role in the development of leukoderma through the production of damage to melanocytes and immunological responses.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!