“… 75 However, due to the peptide-based analogs, the poor brain permeability, short half-life leading to rapid clearance, and low bioabsorption limit the in vivo therapeutic effect. 76 Nonpeptidomimetic inhibitors, showing metabolic stability and sufficient lipophilicity to cross the both barriers of BBB and endosomal membranes, are usually found via high-throughput screening (HTS) and followed by lead optimization. For example, on the basis of isothiourea, a weak BACE1 ligand, the amidine moiety and diaryl amide substituent were modified to provide the high affinity for the continuous hydrophobic subsite of BACE1, as well as a high permeability for oral absorption, and MK-8931 (verubecestat) guanidine containing scaffold was designed ( Figure 3B ).…”