Alzheimer’s disease (AD) is the most common type of dementia. The accumulation of amyloid β (Aβ) peptides is considered to be a causal factor of AD, and β-secretase (BACE1) is a rate-limiting enzyme in Aβ peptide production. Therefore, inhibiting BACE1 should be beneficial as a disease-modifying treatment. Our hit-to-lead SAR efforts identified thiazine 1as a lead, which had a promising in vitroactivity although it possessed high P-gp efflux and hERG inhibition. In parallel with our efforts, scientists at Roche reported a 6-trifluoromethyl oxazine 2that reduced P-gp efflux, albeit still showing high hERG inhibition. Therefore, we commenced to develop centrally active BACE1 inhibitors with reduced hERG inhibition. We designed trifluoromethyl thiazine 3 by replacing the oxygen in 2with sulfur and synthesized it viaa DAST-mediated thiazine ring formation. Thiazine 3showed low P-gp efflux and hERG inhibition without loss of in vitroBACE1 potency, probably due to a reduced pKa value of the amidine group as a result of the electron-withdrawing nature of CF3group. Further optimization of the tail group of the cyano-pyridine led to 4with improved hERG inhibition relative to 3. Thiazine 4showed significant Abreduction in vivoin both mice and dogs. In addition, cardiovascular (CV) safety was evaluated in anesthetized guinea pigs, confirming a sufficient CV safety margin. Since 4 possesses a isothiourea moiety, the potential of reactive metabolite formation was investigated using 14C labelled 4in human hepatocytes. The covalent binding burden, calculated based on the covalent binding and estimated human dose, was found to be less than 1 mg/day.

Trifluoromethyl thiazine-based BACE1 Inhibitors: Synthesis, in vivo efficacy, cardiovascular side effects, and covalent binding burden

2019 Spring National Meeting

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