We previously reported that carvedilol, a brain bioavailable and bioactive antihypertensive agent, significantly reduces brain contents of Alzheimer’s disease (AD)-type β-amyloid (Aβ) oligomers experimentally. Currently, we are exploring clinical applications of carvedilol to prevent or attenuate the progression of AD dementia. However, the potential development of carvedilol for AD is complicated by its cardiovascular activities, including bradycardia and hypotension, particularly among patients already undergoing treatment with other cardiovascular medications. Based on this, using structure-activity relationship (SAR) medicinal chemistry we are developing novel modified carvedilol lead compounds with decreased cardiovascular features for treating AD. Testing commercially available compounds identified from a preliminary screening of a library of carvedilol analogs, we identified 6 bioactive small-molecule compounds that significantly reduce Aβ oligomerization in vitro. Anti-Aβ oligomerization activity was confirmed by circular diachroism and electron microscopy. One compound, (R)-(+)-4-hydroxyphenyl carvedilol, showed improved anti-oligomerization activity and reduced α-1 adrenergic receptor binding activity compared to carvedilol. Short-term proof-of-concept in vivo testing showed that treatment with 1.5 mg/kg/day (R)-(+)-4-hydroxyphenyl carvedilol significantly reduced levels of oligomeric Aβ and total Aβ in the brains of a transgenic mouse model of AD-type Aβ neuropathology without cardiovascular complications. We are currently evaluating the effects of (R)-(+)-4-hydroxyphenyl carvedilol on cardiovascular functions and the attenuation of Aβ-mediated cognitive dysfunction in experimental AD models. Our study provides the critical basis for exploring the bioavailability and pharmacokinetic characteristics of novel cardiovascular lead compounds with enhanced brain activities and reduced adverse events in IND-directed pre-clinical safety assessments and eventually Phase I clinical applications in AD.
Alzheimer’s disease and insulin resistance: translating basic science into clinical applications
