Track topics on Twitter Track topics that are important to you
The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule, p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. A crystallography and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addition of secondary pharmacology screens to refinement delivered lead compounds with improved selectivity, appropriate pharmacodynamics and efficacy. Safety considerations and additional secondary pharmacology screens drove optimization that delivered the drug candidate, MW01-18-150SRM (MW150), currently in early stage clinical trials.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Neurologic Wilson disease is an inherited disease characterized by a copper metabolic disorder that causes damage to many organs, especially the brain. Few studies report the relationships between the...
Herein we report the discovery of a novel series of highly potent and selective mitogen-activated protein kinase kinase 4 (MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signalling pathways that...
Genetic and pharmacological evidence indicates that reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of H...
The previous studies have shown that glial glutamate transporter-1 (GLT-1) participates in cerebral ischemic injury in rats. However, the mechanism involved remains to be elucidated. This study was un...
To evaluate the association between selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) use and risk of fractures in older adults.
Metastatic breast cancer (MBC) remains an incurable disease and despite an improvement of the effect of systemic treatments. After relapse on first-line non-steroidal aromatase inhibitor, ...
The purpose of this research is to determine whether there is more extensive inflammation in the brain of people with clinical evidence of neuropsychiatric syndromes, such as mood disorder...
This study is an investigation of the neurologic, immunologic, and rheumatologic markers of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). PANS is a condition characterized by the...
Investigators are seeking to learn how well different cooling temperatures along with different blood flow pathways to the brain reduce the risk of injury to the brain in participants plan...
This is a phase 2b, double-blind, placebo controlled proof-of-concept study of a an oral small molecule selective inhibitor of p38 alpha kinase, neflamapimod, administered for 24 weeks in ...
Tissue NECROSIS in any area of the brain, including the CEREBRAL HEMISPHERES, the CEREBELLUM, and the BRAIN STEM. Brain infarction is the result of a cascade of events initiated by inadequate blood flow through the brain that is followed by HYPOXIA and HYPOGLYCEMIA in brain tissue. Damage may be temporary, permanent, selective or pan-necrosis.
Acute and chronic neurologic disorders associated with the various neurologic effects of ETHANOL. Primary sites of injury include the brain and peripheral nerves.
Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.
A proline-directed serine/threonine protein kinase which mediates signal transduction from the cell surface to the nucleus. Activation of the enzyme by phosphorylation leads to its translocation into the nucleus where it acts upon specific transcription factors. p40 MAPK and p41 MAPK are isoforms.
Conditions characterized by persistent brain damage or dysfunction as sequelae of cranial trauma. This disorder may result from DIFFUSE AXONAL INJURY; INTRACRANIAL HEMORRHAGES; BRAIN EDEMA; and other conditions. Clinical features may include DEMENTIA; focal neurologic deficits; PERSISTENT VEGETATIVE STATE; AKINETIC MUTISM; or COMA.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
Stress is caused by your perception of situations around you and then the reaction of your body to them. The automatic stress response to unexpected events is known as 'fight or flight'. Discovered by Walter Cannon in 1932, it is the release of h...