Structure-activity relationship study of hydroxyethylamine isostere and P1' site structure of peptide mimetic BACE1 inhibitors

  • Bioorg Med Chem. 2021 Nov 15;50:116459. doi: 10.1016/j.bmc.2021.116459.
Kazuya Kobayashi  1 ,  Takuya Otani  2 ,  Saki Ijiri  2 ,  Yuki Kawasaki  2 ,  Hiroki Matsubara  2 ,  Takahiro Miyagi  2 ,  Taishi Kitajima  2 ,  Risa Iseki  2 ,  Katsuyasu Ishizawa  2 ,  Naoka Shindo  2 ,  Kouta Okawa  2 ,  Kouta Ueda  2 ,  Syun Ando  2 ,  Momoka Kawakita  2 ,  Yasunao Hattori  3 ,  Kenichi Akaji  2
Affiliations
  • 1. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. Electronic address: [email protected].
  • 2. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
  • 3. Center for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
PMID: 34700240 DOI: 10.1016/j.bmc.2021.116459
Abstract

An aromatic substituent has been introduced into a known hydroxyethylamine (HEA)-type BACE1 Inhibitor containing the superior substrate sequence to enhance inhibitory activity. The HEA-type isosteres bearing different hydroxyl group and methyl group configurations were prepared through a branched synthesis approach using intra- and inter-molecular epoxide opening reactions. The effect of their configuration was evaluated, showing that an R-configuration improved the inhibitory activity, while introduction of a methyl group on the isostere decreased the activity. Based on the non-substituted isostere with an R-configuration, 21 derivatives containing various substituents at the P1' site were synthesized. Our evaluation of the derivatives showed that the structure of the P1' site had a clear effect on activity, and highly potent inhibitor 40g, which showed sub-micromolar activity against recombinant BACE1 (rBACE1), was identified. The docking simulation of 40g with rBACE1 suggested that a carboxymethyl group at the para-position of the P1' benzene ring interacted with Lys285 in the S1' pocket.

Keywords
Alzheimer’s disease; BACE1; Hydroxyethylamine; Inhibitor; Peptide mimetics.
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