2. Academic Validation
  3. Design, synthesis, and evaluation of new vanin-1 inhibitors based on RR6

Design, synthesis, and evaluation of new vanin-1 inhibitors based on RR6

  • Bioorg Med Chem. 2022 Jul 1;65:116791. doi: 10.1016/j.bmc.2022.116791.
Hiroki Yoneyama 1,  Keiko Hosohata 2,  Denan Jin 3,  Iroha Yoshida 1,  Miyui Toyoda 1,  Ikuko Kitamura 1,  Shinji Takai 3,  Yoshihide Usami 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1Nasahara, Takatsuki City, Osaka 569-1094, Japan.
  • 2 Education and Research Center of Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1Nasahara, Takatsuki City, Osaka 569-1094, Japan.
  • 3 Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
  • 4 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1Nasahara, Takatsuki City, Osaka 569-1094, Japan. Electronic address: yoshihide.usami@ompu.ac.jp.
PMID: 35537325 DOI: 10.1016/j.bmc.2022.116791
Abstract

Fourteen novel vanin-1 inhibitors coded OMP-# were designed from RR6 and successfully synthesized by a nucleophilic addition-elimination reaction of the pantetheinic acid-derived Weinreb amide as a key step under Barbier conditions. The synthesized OMP compounds exhibited inhibitory activity against human serum vanin-1 in vitro. Among the synthesized compounds, OMP-7, which possesses a trifluoromethoxy group at the para-position on the phenyl ring, exhibited the most potent activity, approximately 20 times that of the mother compound RR6. OMP-7 was further subjected to an in vivo assay using a normal hamster. More potent activity was observed than that of RR6 against both serum and renal vanin-1. The activity lasted for 4 h after injection against serum vanin-1 and 1 h after injection against renal vanin-1, whereas RR6 did not show the desired activity.

Keywords

Barbier reaction condition; Inhibitor; Pantetheine; RR6; Substituted phenyl group; Vanin-1.

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