BACE1-IN-5 (Compound 15), a potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, demonstrates significant efficacy with an IC50 of 9.1 nM for BACE1 inhibition and an impressive IC50 of 0.82 nM against cellular amyloid-β (Aβ) production. Additionally, it is engineered to enhance hERG inhibition and P-gp efflux, indicating its optimized medicinal chemistry profile [1].

Cellular β-Amyloid:0.82 nM , BACE1:9.1 nM

Treatment with BACE1-IN-5 (Compound 15), administered orally at doses ranging from 1-3 mg/kg to male ICR mice for durations of 2-6 hours, significantly and dose-dependently decreases total amyloid-beta (Aβ) levels. At a dose of 1 mg/kg, it reduces total Aβ by 76% within 4 hours, correlating with a free brain concentration of 4.1 ng/mL (8.9 nM). This compound also exhibits a K_p,uu value of 1.3 at the 4-hour mark and a 1 mg/kg dose. When the dosage is increased to 3 mg/kg, BACE1-IN-5 achieves a maximal Aβ reduction of 87%, corresponding to a free brain concentration of 9.5 ng/mL (21 nM).