2. Academic Validation
  3. Structure-activity relationship study of hydroxyethylamine isostere and P1' site structure of peptide mimetic BACE1 inhibitors

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

Affiliations

  • 1 Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. Electronic address: kkoba@mb.kyoto-phu.ac.jp.
  • 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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