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

• Published in: Journal of medicinal chemistry Vol. 61; no. 3; pp. 1355 - 1374
• Main Authors: Ren, Qingyun, Liu, Xinchang, Yan, Guanghua, Nie, Biao, Zou, Zhifu, Li, Jing, Chen, Yunfu, Wei, Yu, Huang, Jianzhou, Luo, Zhonghua, Gu, Baohua, Goldmann, Siegfried, Zhang, Jiancun, Zhang, Yingjun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.02.2018; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Capsid - drug effects; Chemistry, Medicinal; Dogs; Drug Discovery; Hepatitis B virus - drug effects; Hepatitis B virus - metabolism; Life Sciences & Biomedicine; Male; Molecular Docking Simulation; Morpholines - chemistry; Morpholines - pharmacokinetics; Morpholines - pharmacology; Pharmacology & Pharmacy; Propionates - chemistry; Propionates - pharmacokinetics; Propionates - pharmacology; Protein Conformation; Pyrimidines - pharmacology; Rats; Science & Technology; Stereoisomerism; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Tissue Distribution; PRECLINICAL CHARACTERIZATION; IN-VITRO; REPLICATION; HERG; NUCLEOCAPSIDS; ANALOGS; COMPOUND; INFECTION; PROTEINS; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01914

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.