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Development of an Anti-Hepatitis B Virus (HBV) Agent Through the Structure-Activity Relationship of the Interferon-Like Small Compound CDM-3008

Development of an Anti-Hepatitis B Virus (HBV) Agent Through the Structure-Activity Relationship of the Interferon-Like Small Compound CDM-3008

Nobuaki Takahashi, Kyohei Hayashi, Yusuke Nakagawa, Yutaka Furutani, Mariko Toguchi, Yumi Shiozaki-Sato, Masayuki Sudoh, Soichi Kojima, Hideaki Kakeya

Bioorg Med Chem. 2019 Feb 1;27(3):470-478.

PMID: 30552008

Abstract:

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).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP691868889	RO8191		691868-88-9	Price

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