From potent and selective inhibitors of GSK3beta displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.
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http://dx.doi.org/10.1016/j.bmcl.2010.01.132 | DOI Listing |
Background: Alzheimer's disease (AD) agitation is a distressing neuropsychiatric symptom characterized by excessive motor activity, verbal aggression, or physical aggression. Agitation is one of the causes of caregiver distress, increased morbidity and mortality, and early institutionalization in patients with AD. Current medications used for the management of agitation have modest efficacy and have substantial side effects.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Patiala, India.
Background: Neuroinflammation plays an important role in progression of Alzheimer's disease (AD). Interlukin-6 (IL-6) is well identified marker in initiating and regulating inflammation, and formation of senile plaques in brain. Therefore, simultaneous inhibition of both IL-6 and acetylcholinesterase (AChE) may be an effective strategy for AD.
View Article and Find Full Text PDFBackground: DYRK1A overexpression, common in neurodegenerative diseases like Alzheimer's (AD), contributes to neurofibrillary tangles via Tau protein hyperphosphorylation and amyloid plaque formation, key AD hallmarks. Therefore, DYRK1A has been regarded as a novel target for neurodegenerative diseases. However, developing DYRK1A selective inhibitors has been a difficult challenge due to the highly conserved ATP-binding site of protein kinases, particularly among the CMGC family.
View Article and Find Full Text PDFBackground: TREM2 is a lipid-sensing receptor expressed by microglial sub-populations within neuropathological microenvironments, whose downstream signaling promotes microglial survival, plasticity, and migration. Multiple loss-of-function variants strongly implicate TREM2 as a key regulator of Alzheimer's disease (AD) risk. Accordingly, TREM2 antibodies are currently in development to evaluate the therapeutic potential of TREM2 agonism in neurodegenerative diseases.
View Article and Find Full Text PDFBackground: Progranulin (GRN) plays a critical role in familial frontotemporal dementia (fFTD), where GRN haploinsufficiency leads to reduction in PGRN levels in the brain, resulting in degeneration of neurons in the frontal lobe of brain responsible for personality, language, and behavior. FTD is the most common dementia in people under 60. Sortilin (Sort1), expressed by neurons, endocytoses, and delivers PGRN rapidly to lysosomes for degradation.
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