ABSTRACT
Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1ß, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Dry Eye Syndromes , Animals , Mice , Rabbits , Conjunctiva/metabolism , Cornea , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/genetics , Dry Eye Syndromes/metabolism , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Pyrimidines/metabolism , Solubility , Tears/metabolismSubject(s)
Alzheimer Disease/pathology , tau Proteins/antagonists & inhibitors , Acetylation , Alzheimer Disease/drug therapy , Animals , Humans , Methylene Blue/analogs & derivatives , Methylene Blue/therapeutic use , Mice , Salicylates/therapeutic use , Severity of Illness Index , tau Proteins/metabolismABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss and cognitive impairment. As this disease is becoming a serious global health issue, development of disease modifying therapeutics is urgently required. AD is characterized by deposits of two protein, amyloid ß and tau. Although amyloid ß-based therapeutics have been extensively investigated so far, tau has also received great attention as one of promising molecular targets for AD. In this review, a variety of tau-directed strategies to rescue tau-mediated neurotoxicity will be reviewed especially focusing on small molecules. Subsequently, recent patents published from 2014 to 2018 that integrate efforts to develop tau-directed small molecules for the treatment of AD will be reviewed.
