β-Secretase (BACE1: β-site Amyloid precursor protein Cleaving Enzyme 1) is an important therapeutic target for Alzheimer’s disease, because it concerns initial step in the production of amyloid β protein, which has been considered to be one of the causal agents for the disease. Recently, many small molecule BACE1 inhibitors containing a non-planar cyclic amidine structure 1 has been reported, and the structure is expected as a promising pharmacophore. Based on the amidine structure, we devised N-amidino nitrogen-containing ring structure 2. In this work, we designed and synthesized N-amidino piperidine- and N-amidino pyrrolidine-type BACE1 inhibitors 3 and 4. In the synthesis of N-amidino pipridine-type inhibitors, 3,6-cis-2,3,6-trisubstituted piperidine was constructed from alanine using the reported procedure and various substituents were introduced at its 3 and/or 6 position. Evaluation of their inhibitory activity suggested that bulky hydrophobic substituent was appropriate for their activity, although the activity value was not sufficient. In the synthesis of N-amidino pyrrolidine-type inhibitors, hydroxyproline was used as a starting material, and hydrophobic substituents were connected with the hydroxyl group and carboxyl group. As with N-amidino piperidine-type inhibitors, bulky substituent was appropriate, and we found out the derivative 5 with week but clear inhibitory activity for BACE1. This presentation will described synthesis and evaluation of these BACE1 inihibtors.

Synthesis and evaluation of novel BACE1 inhibitors based on the N-amidino nitrogen-containing ring structure

256th National Meeting (2018)

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