Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.

Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD.

Inequalities in the access to diagnosis and treatment of obstructive sleep apnea in Brazil: a cross-sectional study.

Study Objectives: Obstructive sleep apnea (OSA) is highly prevalent, and positive airway pressure (PAP) therapy is the primary treatment. This study aimed to assess the diagnostic and PAP treatment resources for OSA within Brazil's Unified Health System and to identify potential inequalities and gaps.

Methods: A structured survey was sent to members of the Brazilian Sleep Association and the Brazilian Association of Sleep Medicine to identify sleep laboratories providing OSA diagnosis and/or treatment within Brazil's Unified Health System.

Legal action for access to resources inefficiently made available in health care systems in Brazil: a case study on obstructive sleep apnea.

Objective: Obstructive sleep apnea (OSA) is a highly prevalent chronic disease, associated with morbidity and mortality. Although effective treatment for OSA is commercially available, their provision is not guaranteed by lines of care throughout Brazil, making legal action necessary. This study aimed at presenting data related to the volume of legal proceedings regarding the access to diagnosis and treatment of OSA in Brazil.

Discovery of Dual Aβ/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis.

From Combinations to Single-Molecule Polypharmacology-Cromolyn-Ibuprofen Conjugates for Alzheimer's Disease.

Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets.

Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy.

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs.

Molecular Hybridization as a Tool for Designing Multitarget Drug Candidates for Complex Diseases.

Molecular hybridization is a well-exploited medicinal chemistry strategy that aims to combine two molecules (or parts of them) in a new, single chemical entity. Recently, it has been recognized as an effective approach to design ligands able to modulate multiple targets of interest. Hybrid compounds can be obtained by linking (presence of a linker) or framework integration (merging or fusing) strategies.