Development of an anti-hepatitis B virus (HBV) agent through the structure-activity relationship of the interferon-like small compound CDM-3008

• Published in: Bioorganic & medicinal chemistry 2019-02, Vol.27 (3), p.470-478
• Main Authors: Takahashi, Nobuaki, Hayashi, Kyohei, Nakagawa, Yusuke, Furutani, Yutaka, Toguchi, Mariko, Shiozaki-Sato, Yumi, Sudoh, Masayuki, Kojima, Soichi, Kakeya, Hideaki
• Format: Article
• Language: English
• Subjects: Animals; Anti-HBV agent; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cells, Cultured; Dose-Response Relationship, Drug; Drug Development; Hepatitis B virus; Hepatitis B virus - drug effects; Humans; Interferon; Mice; Microsomes, Liver - chemistry; Microsomes, Liver - metabolism; Molecular Structure; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.11.039

[Display omitted] Hepatitis B, a viral infectious disease caused by hepatitis B virus (HBV), is a life-threatening disease that leads liver cirrhosis and liver cancer. Because the current treatments for HBV, such as an interferon (IFN) formulation or nucleoside/nucleotide analogues, are not sufficient, the development of a more effective agent for HBV is urgent required. CDM-3008 (1, 2-(2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole) (RO8191)) is a small molecule with an imidazo[1,2-a][1,8]naphthyridine scaffold that shows anti-HCV activity with an IFN-like effect. Here, we report that 1 was also effective for HBV, although the solubility and metabolic stability were insufficient for clinical use. Through the structure-activity relationship (SAR), we discovered that CDM-3032 (11, N-(piperidine-4-yl)-2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxamide hydrochloride) was more soluble than 1 (>30 mg/mL for 11 versus 0.92 mg/mL for 1). In addition, the half-life period of 11 was dramatically improved in both mouse and human hepatic microsomes (T1/2, >120 min versus 58.2 min in mouse, and >120 min versus 34.1 min in human, for 11 and 1, respectively).