Discovery of ASP5286: A novel non-immunosuppressive cyclophilin inhibitor for the treatment of HCV

  • Bioorg Med Chem Lett. 2020 Aug 15;30(16):127308. doi: 10.1016/j.bmcl.2020.127308.
Takuya Makino  1 ,  Seiji Yoshimura  2 ,  Masahiro Neya  2 ,  Toshio Yamanaka  2 ,  Masae Sawada  2 ,  Eisaku Tsujii  2 ,  David Barrett  2
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: [email protected].
  • 2. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
PMID: 32631528 DOI: 10.1016/j.bmcl.2020.127308
Abstract

Evidence indicates that hepatitis C virus (HCV) utilizes cellular Cyclophilin proteins in its replication, and Cyclophilin inhibitors represent a new class of anti-HCV agents. We have established an efficient synthetic methodology to generate FR901459 derivatives via N, O-acyl migration reaction while avoiding total synthesis. Through a detailed structure-activity relationship study, we improved anti-HCV activity while decreasing immunosuppressive activity. Additionally, we discovered the importance of substitution at the 3 position for not only improving anti-HCV activity but also pharmacokinetic profile. Finally, by striking an appropriate balance between potency, solubility, and permeability, we discovered ASP5286 (13) as a potential clinical candidate for anti-HCV therapy.

Keywords
Aqueous solubility; Cyclophilin inhibitor; Cyclosporin A; FR901459; HCV; N,O-acyl migration; PK; Semi-synthesis.
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