Discovery of a novel 9-position modified second-generation anti-HCV candidate via bioconversion and semi-synthesis of FR901459

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 18; pp. 127423 - 127429
• Main Authors: Makino, Takuya, Ishida, Junya, Yamanaka, Toshio, Ohki, Hidenori, Uchida, Masao, Sawada, Masae, Barrett, David
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.09.2020; Elsevier
• Subjects: Bioconversion; C-alkylation; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cyclophilin inhibitor; Cyclosporin A; Direct modification; FR901459; HCV; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Semi-synthesis; C-alkylation; Direct modification; Cyclophilin inhibitor; Bioconversion; HCV; FR901459; Cyclosporin A; PK; Semi-synthesis; NIM811; HEPATITIS-C-VIRUS; ALPHA; CYCLOSPORINE-A; REPLICATION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127423

[Display omitted] 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.