Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure

Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 beta-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1' position further improved the activity.

Automated summary

In this study, a cross-linked structure between the P1 and P3 side chains was introduced in the inhibitor of BACE1 to enhance inhibitory activity. Through the synthesis and evaluation of fragments with different side chain lengths, a 13-membered ring with a dimethyl branched substituent at the P3 beta-position was found to be optimal and significantly more active. The introduction of a 4-carboxymethylphenyl group at the P1' position further improved the activity of the inhibitor.