Abstract: β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease whose function is essential for the production of the neurotoxic β-amyloid (Aβ) peptide.  Aβ is widely considered to play a critical role in the etiology of Alzheimer’s disease, and consequently the inhibition of BACE1 activity is a compelling target for this chronic neurodegenerative disease. Previous BACE inhibitors have utilized thiazine warheads as substrates to engage the bi-aspartate binding pocket of the BACE1 enzyme.  Our team targeted the synthesis of cyclopropylthiazines as an alternative aspartate binding chemotype. The resulting molecules demonstrated significant activity on both biochemical and cellular inhibition of BACE1 and lowered brain and CSF Aβ levels in rat phamacodynamic studies.  The chemistry required to access the cyclopropylthiazines was challenging to develop, and this poster will present both the successful and unsuccessful synthetic approaches.  Additionally, the poster will include an x-ray co-crystal structure of a lead inhibitor with BACE1 that supports the assigned stereochemistry of these new inhibitors.<br/>

Cyclopropylthiazines as potent BACE1 inhibitors for Alzheimer’s disease: Challenging chemistry and <i>in-vivo</i> data of this new pre-clinical series

253rd National Meeting (2017)

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Cyclopropylthiazines as potent BACE1 inhibitors for Alzheimer’s disease: Challenging chemistry and in-vivo data of this new pre-clinical series