2. Academic Validation
  3. Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors

Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors

  • ChemMedChem. 2018 Mar 6;13(5):411-421. doi: 10.1002/cmdc.201700645.
Masaki Ohtawa 1,  Shiho Arima 1,  Naoki Ichida 1,  Tomiaki Terayama 1,  Hironao Ohno 1,  Takaya Yamazaki 1,  Taichi Ohshiro 2,  Noriko Sato 3,  Satoshi Omura 4,  Hiroshi Tomoda 2,  Tohru Nagamitsu 1
Affiliations

Affiliations

  • 1 Department of Synthetic Natural Products Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
  • 2 Department of Microbial Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
  • 3 School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
  • 4 Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
PMID: 29323466 DOI: 10.1002/cmdc.201700645
Abstract

Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO-1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O-acyltransferase 2 (SOAT2). To aid in the development of new cholesterol-lowering or anti-atherosclerotic agents, new A-ring simplified pyripyropene A analogues have been designed and synthesized based on total synthesis, and the results of structure-activity relationship studies of pyripyropene A. Among the analogues, two A-ring simplified pyripyropene A analogues exhibited equally efficient SOAT2 inhibitory activity to that of natural pyripyropene A. These new analogues are the most potent and selective SOAT2 inhibitors to be used as synthetic compounds and attractive seed compounds for the development of drug for dyslipidemia, including atherosclerotic disease and steatosis.

Keywords

drug discovery; inhibitors; natural products; structure-activity relationships; total synthesis.

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