Author: Zhao, Shujie ; Cherukupalli, Srinivasulu ; Ma, Yue ; Tavis, John E ; Bradley, Daniel P ; Liu, Xinyong ; Ren, Yujie ; Li, Qilan ; Zhan, Peng ; Woodson, Molly E

GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitroanti-HBV activity and low cytotoxicity were observed for compound 4r (EC₅₀ = 0.20 ± 0.00 μM, CC₅₀ > 87.03 μM), which was more potent than the positive control lamivudine (EC₅₀ = 0.37 ± 0.04 μM, CC₅₀ > 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC₅₀ = 0.045 ± 0.01 μM, CC₅₀ > 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo.

08 Feb 2018·Journal of Medicinal ChemistryQ1 · MEDICINE

3-((R)-4-(((R)-6-(2-Bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic Acid (HEC72702), a Novel Hepatitis B Virus Capsid Inhibitor Based on Clinical Candidate GLS4

Q1 · MEDICINE

Article

Author: Goldmann, Siegfried ; Ren, Qingyun ; Liu, Xinchang ; Zhang, Yingjun ; Li, Jing ; Wei, Yu ; Luo, Zhonghua ; Zhang, Jiancun ; Chen, Yunfu ; Nie, Biao ; Zou, Zhifu ; Yan, Guanghua ; Gu, Baohua ; Huang, Jianzhou

The inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. On the basis of the preclinical properties and clinical results of GLS4, we carried out further investigation to seek a better candidate compound with appropriate anti-HBV potency, reduced hERG activity, decreased CYP enzyme induction, and improved pharmacokinetic (PK) properties. To this end, we have successfully found that morpholine carboxyl analogues with comparable anti-HBV activities to that of GLS4 showed decreased hERG activities, but they displayed strong CYP3A4 induction in a concentration-dependent manner, except for morpholine propionic acid analogues. After several rounds of modification, compound 58 (HEC72702), which had an (R)-morpholine-2-propionic acid at the C6 position of its dihydropyrimidine core ring, was found to display no induction of the CYP1A2, CYP3A4, or CYP2B6 enzyme at the high concentration of 10 μM. In particular, it demonstrated a good systemic exposure and high oral bioavailability and achieved a viral-load reduction greater than 2 log in a hydrodynamic-injected (HDI) HBV mouse model and has now been selected for further development.

01 Aug 2015·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Development of novel hepatitis B virus capsid inhibitor using in silico screening

Q3 · BIOLOGY

Article

Author: Yano, Yoshihiko ; Tanahashi, Toshihito ; Murakami, Yoshiki ; Iwadate, Mitsuo ; Hayakawa, Michiyo ; Enomoto, Masaru ; Umeyama, Hideaki ; Kawada, Norifumi ; Tamori, Akihiro

Antiviral therapy for chronic hepatitis B that uses nucleos(t)ide analogue is considered effective. However, most drugs of this class frequently result in viral relapse after cessation of therapy as well as the emergence of resistance, thereby limiting their clinical use. In order to increase the therapeutic efficiency of chronic hepatitis B treatments, it is important to survey novel (chemical) reagents targeting other stages of the viral replication process. The aim of this study was to identify novel capsid inhibitor candidates using in silico screening. We discovered four such candidates that decreased the levels of HBV DNA and HBsAg in vitro. These four capsid inhibitor candidates did not induce cell toxicity even at high concentrations. Results from docking simulation showed that the candidates bounded with high affinity with the capsid protein hydrophobic binding site. Identifying direct acting HBV core protein inhibitors increases the likelihood that novel medicines can be developed that allows the combination of novel anti-viral drugs and nucleos(t)ide analogue or interferon for HBV treatment.

100 Deals associated with Hepatitis B virus immune globulin(Grifols)

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Indication	Country/Location	Organization	Date
Hepatitis B	ES	Grifols SA	01 Apr 2008

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