Evidence that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in the virus replication cycle has increased attention on cyclophilin inhibitors as attractive therapeutic targets in the treatment of HCV. Previous reports have described a number of non-immunosuppressive cyclophilin inhibitors, most of which require many synthetic steps for their preparation. Sasamura et al. have previously reported the isolation of bioconversion derivative 4. This analog is a convenient starting point for optimization due to the presence of the readily modifiable primary hydroxyl group and because it shows moderate anti-HCV activity and decreased immunosuppressive activity. We have also established an efficient C-alkylation reaction at the 3-position. Through a detailed structure-activity relationship study, we discovered a new type of clinical candidate 14 which requires a short synthetic process and has potent anti-HCV activity and reduced immunosuppressive activity, as well as improved aqueous solubility and pharmacokinetics.

01 Aug 2020·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Sawada, Masae ; Yoshimura, Seiji ; Yamanaka, Toshio ; Makino, Takuya ; Barrett, David ; Tsujii, Eisaku ; Neya, Masahiro

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.

01 Jul 2020·Bioorganic & Medicinal Chemistry Letters

Development of an efficient semisynthetic modification of FR901459 via a novel regioselective N, O-acyl migration

Article

Author: Barrett, David ; Yamanaka, Toshio ; Yoshimura, Seiji ; Sawada, Masae ; Makino, Takuya

HCV utilizes cellular protein cyclophilins in the virus replication cycle and cyclophilin inhibitors have become a new class of anti-HCV agents. In our screening of natural products, we identified a unique cyclosporin analogue, FR901459, as a cyclophilin inhibitor with potent anti-HCV activity. In this work, we developed an efficient synthetic methodology to prepare FR901459 derivatives via an N, O-acyl migration reaction. This method allows us to efficiently manipulate the amino acid residues at the 3 position while avoiding lengthy total synthesis for each compound. By using this methodology, we discovered 4, which has superior anti-HCV activity and decreased immunosuppressive activity compared to FR901459.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	Japan	Fujisawa Pharmaceutical Co., Ltd.	-

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