Development of Carvedilol Analogs with Anti-Oligomerization Activity for Treating AD (P04.191)

Abstract

Objective: This study is designed to use structure activity relationship (SAR) approach to identify novel carvedilol analogs lacking α1/β2 adrenergic receptors activity while enhancing the structural features essential for anti-Aβ oligomerization activity for treating Alzheimer9s disease (AD). Background Carvedilol is a brain bioavailable and bioactive small antihypertensive drug. We found chronic carvedilol treatment significantly reduced the brain content of oligomeric Aβ and attenuated cognitive deterioration in two transgenic mouse models of AD. Our preclinical studies suggest that carvedilol interferes with neuropathologic, biochemical and electrophysiological mechanisms underlying cognitive deterioration in AD and implicate its potential in AD treatment. Carvedilol has now progressed to a phase IIa clinical trial. Despite strong evidence suggesting that carvedilol might be developed as a novel efficacious treatment for AD, the cardiovascular effects of carvedilol including potential for hypotension and bradycardia complicate its use in normotensive AD subjects and in AD subjects already taking β-blockers. Design/Methods: Photo-induced cross-linking of unmodified protein (PICUP), Circular dichroism (CD) and electron microscopy (EM) examination were used to test the efficacy of carvedilol analogs in interfering with Aβ oligomerization; Radioligand competition binding assay were used to evaluate the binding affinity of carvedilol analogs to α1/β2 adrenergic receptors. Results: We tested 15 carvedilol analogs and identified 6 compounds with improved anti-oligomerization activity and reduced α1/β2 adrenergic receptors activities. Short-term preclinical testing using TgCRND8 mouse model of AD showed that one of the compounds can significantly reduce total Aβ content as well as Aβ oligomer in the brain following 3 weeks short-term treatment. Conclusions: We tested 15 carvedilol analogs and identified 6 compounds that have improved anti-oligomerization activity and reduced α1/β2 adrenergic receptors binding activities. Short-term preclinical testing using TgCRND8 mouse model of AD showed that one of the compounds can significantly reduce total Aβ content as well as Aβ oligomer in the brain following 3 weeks short-term treatment. Supported by: Our study can lead to the development of novel lead compounds for IND-directed pre-clinical safety assessment and Phase I clinical trial for Alzheimer9s disease therapy. Disclosure: Dr. Pasinetti has nothing to disclose. Dr. Ono has nothing to disclose. Dr. Wang has nothing to disclose.