Evolution of Tertiary Carbinamine BACE‐1 Inhibitors: Aβ Reduction in Rhesus CSF upon Oral Dosing

Turning up the BACE: Incorporation of an isonicotinic core into oxadiazolyl tertiary carbinamine-based inhibitors of BACE-1 has led to the identification of an exquisitely potent inhibitor, which displays good Papp and low susceptibility to the P-gp efflux pump. Upon twice daily oral administration to monkeys, co-dosed with ritonavir, this inhibitor was shown to penetrate the CNS and lower Aβ42 levels in the CSF by >40 % over the 3 day course of the experiment.