In order to explore whether selective deuteration of sildenafil affects selectivity and efficacy of the drug, the inhibitory activity of sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl-sulfonyl] -4-methylpiperazine citrate, CAS 139755-83-2) and three deuterated sildenafil derivatives, D8-piperazine-sildenafil (BDD-10402), D3-methyl-D8-piperazine-sildenafil (BDD-10403) and D5-ethoxy-Sildenafil (BDD-10406) against phosphodiesterases 1-6 was compared. Furthermore, the relaxant effect of sildenafil and its deuterated derivatives in a contractility assay on rabbit corpus cavernosum strips from New Zealand rabbits was investigated. BDD-10406 exhibits a 2-fold higher selectivity for phosphodiesterase 5 versus phosphodiesterase 6 than sildenafil. BDD-10406 and sildenafil inhibited cGMP formation with IC50 values of 6 nmol/L and 9 nmol/L, respectively. The corresponding IC80 values for BDD-10406 and Sildenafil were 33 nmol/L and 40 nmol/L, respectively. Sildenafil, BDD-10402, BDD-10403 and BDD-10406 relaxed the rabbit corpus cavernosum strips in a dose-dependent manner with ED50 values of 245 nmol/L, 91 nmol/L, 121 nmol/L and 85 nmol/L, respectively. Deuteration of sildenafil on the ethoxy group (BDD-10406) leads to enhanced selectivity for phosphodiesterase 5 versus phosphodiesterase 6 and higher efficacy in vitro. This is the first example of a deuteration effect on the inhibitory activity of a reversible enzyme inhibitor.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1055/s-0031-1296622 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Biochemical osteomalacia in adults undergoing vitamin D testing in the North-East of Scotland.
Ann Clin Biochem
January 2025
Department of Clinical Biochemistry, Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, Scotland.
Background: International guidelines give greatly varying definitions of 25-hydroxyvitamin D (25OHD) insufficiency and deficiency. Vitamin D testing is increasing despite 2016 UK guidance for adults advising routine vitamin D supplementation October-March and year-round for high risk groups. A service evaluation of vitamin D testing and biochemical osteomalacia in the North-East of Scotland (57-58°N) could inform definitions and testing guidance.
View Article and Find Full Text PDFCXCL-10 in Cerebrospinal Fluid Detects Neuroinflammation in HTLV-1-Associated Myelopathy with High Accuracy.
Viruses
January 2025
Programa de Pós-Graduação em Doenças Infecciosas e Parasitárias, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-913, Brazil.
Background And Objectives: HTLV-1-associated myelopathy (HAM) is a chronic progressive inflammatory disease of the spinal cord. This study assesses the diagnostic accuracy of the neuroinflammatory biomarkers neopterin and cysteine-X-cysteine motif chemokine ligand 10 (CXCL-10) in cerebrospinal fluid (CSF) for HAM.
Methods: CSF samples from 75 patients with neurological disorders-33 with HAM (Group A), 19 HTLV-1-seronegative with other neuroinflammatory diseases (Group B), and 23 HTLV-1-seronegative with non-neuroinflammatory diseases (Group C)-were retrospectively evaluated.
Vitamin D: Evidence-Based Health Benefits and Recommendations for Population Guidelines.
Nutrients
January 2025
Orthomolecular Medicine News Service, Columbia, SC 29212, USA.
Vitamin D offers numerous under-recognized health benefits beyond its well-known role in musculoskeletal health. It is vital for extra-renal tissues, prenatal health, brain function, immunity, pregnancy, cancer prevention, and cardiovascular health. Existing guidelines issued by governmental and health organizations are bone-centric and largely overlook the abovementioned extra-skeletal benefits and optimal thresholds for vitamin D.
View Article and Find Full Text PDFBaseline Vitamin D Levels on Quality of Life and Pain Perception Among Patients with Chronic Pain with Long-Term Prescription Opioid Use: A Prospective Study.
J Clin Med
January 2025
Clinic of Anaesthesiology and Intensive Care, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania.
To investigate the correlation between baseline serum concentrations of 25-hydroxyvitamin D (25-OHD) and quality of life (QoL), as well as pain perception in patients with chronic pain with long-term prescription opioid usage before opioid detoxification. We prospectively studied 45 patients with chronic pain with long-term prescription opioid usage who were selected for elective detoxification. Baseline serum 25-OHD levels were measured prior to detoxification, classifying patients as either vitamin D deficient (<75 nmol/L) or sufficient (≥75 nmol/L).
View Article and Find Full Text PDFDerivation of human toxicokinetic parameters and internal threshold of toxicological concern for tenuazonic acid through a human intervention trial and hierarchical Bayesian population modeling.
J Expo Sci Environ Epidemiol
January 2025
Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Background: Tenuazonic acid (TeA), a mycotoxin produced by Alternaria alternata, contaminates various food commodities and is known to cause acute and chronic health effects. However, the lack of human toxicokinetic (TK) data and the reliance on external exposure estimates have stalled a comprehensive risk assessment for TeA.
Objective: To bridge this gap, a human TK trial and population-based TK (PopTK) modeling were applied to determine human TK parameters of TeA, and the results were applied for risk screening using population biomonitoring data and threshold of toxicological concern (TTC)-based approaches.
Want 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!