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CaML: Chemistry-informed machine learning explains mutual changes between protein conformations and calcium ions in calcium-binding proteins using structural and topological features.
Protein Sci
February 2025
Department of Physics, University of Washington, Seattle, Washington, USA.
Proteins' flexibility is a feature in communicating changes in cell signaling instigated by binding with secondary messengers, such as calcium ions, associated with the coordination of muscle contraction, neurotransmitter release, and gene expression. When binding with the disordered parts of a protein, calcium ions must balance their charge states with the shape of calcium-binding proteins and their versatile pool of partners depending on the circumstances they transmit. Accurately determining the ionic charges of those ions is essential for understanding their role in such processes.
View Article and Find Full Text PDFFuture perspectives for PDE5 inhibitors bridging the gap between cardiovascular health and psychological status.
Basic Clin Androl
January 2025
Chair of Endocrinology and Medical Sexology (ENDOSEX), Dept. of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, Rome, 00133, Italy.
The serendipitous discovery that inhibiting type 5 phosphodiesterase (PDE5) using sildenafil, a potent PDE5 inhibitor (PDE5i) initially developed for cardioprotection, introduced the possibility of orally managing erectile dysfunction (ED) led to an increase in research data, which are currently considered groundbreaking for the new discipline of sexual medicine. Findings from a number of laboratories and clinics around the world unanimously demonstrated the following: (i) the major cause of ED is directly or indirectly related to cardiovascular disease (CVD); (ii) ED and CVDs share the same risk factors, which are related mainly to lifestyle choices; (iii) the first therapeutic approach to both ED and CVDs is to transform harmful lifestyles into virtuous lifestyles; and (iv) PDE5is in general, particularly sildenafil, are very safe, if not protective, for use in CVD patients. However, the use of PDE5is has faced several challenges.
View Article and Find Full Text PDFIdentification of a 7H-pyrrolo[2,3-d]pyrimidin derivatives as selective type II c-Met/Axl inhibitors with potent antitumor efficacy.
Bioorg Chem
January 2025
Center for Preclinical Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:
In this study, we reported the discovery of a novel type II c-Met/Axl inhibitor, characterized by using 4-amino-7H-pyrrolo[2,3-d]pyrimidine as a hinge region binder. Through a systematic exploration of the structure-activity relationship, based on the clinically reported c-Met inhibitor BMS-777607, we identified the optimized compound 22a. 22a exhibited remarkable potency against c-Met and Axl kinases, with IC values of 1 nM and 10 nM, respectively, and demonstrated over 100-fold selectivity to other members of the TAM subfamily.
View Article and Find Full Text PDFDiscovery of highly oxygenated cytochalasans with antiproliferative activity from an endophytic fungus Boeremia exigua.
Bioorg Chem
January 2025
Anhui Province Key Laboratory of Bioactive Natural Products, School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012 China; Science & Technology Industrial Parks of Anhui University of Chinese Medicine, Hefei 230012 China. Electronic address:
Eleven cytochalasans (1-11), including six undescribed analogues (1-3 and 5-7) and a new natural product (4), were obtained from the endophytic fungus Boeremia exigua. Their structures and absolute configurations were determined by a combination of extensive spectroscopic techniques, electron circular dichroism (ECD), and single-crystal X-ray diffraction. Boerelasin E (1) represented the first cytochalasan possessing a cis-configured Δ double bond.
View Article and Find Full Text PDFIntranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial.
Lancet Neurol
February 2025
Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada. Electronic address:
Background: No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, double-blind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia.
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