Medi 60-Rapid P1 Sar Of Brain Penetrant Tertiary Carbinamine Derived Bace Inhibitors

This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. Extensive SAR studies led to the identification of a potent BACE inhibitor which is twofold more potent in vitro compared to the lead compound. Significant lowering of CSF Aβ40 was observed in a cisterna magna ported rhesus monkey model with the administration of compound 3.