期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 3, 页码 470-478出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.11.039
关键词
Hepatitis B virus; Anti-HBV agent; Interferon; Structure-activity relationship
资金
- Japan Society for the Promotion of Science (JSPS)
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- Japan Agency for Medical Research and Development (AMED) [JP17fk0310112, JP18fk0310112, JP17fk03101120401, JP18fk03101120002]
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-alpha][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole) (RO8191)) is a small molecule with an imidazo[1,2-alpha][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-alpha][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).
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