5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors

• Published in: European journal of medicinal chemistry 2019-02, Vol.164, p.179-192
• Main Authors: Tang, Jing, Huber, Andrew D., Pineda, Dallas L., Boschert, Kelsey N., Wolf, Jennifer J., Kankanala, Jayakanth, Xie, Jiashu, Sarafianos, Stefan G., Wang, Zhengqiang
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Biological Availability; Capsid - drug effects; Capsid - metabolism; Hepatitis B virus - metabolism; Hepatitis B virus - ultrastructure; Humans; Protein Binding; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - pharmacology; Thiophenes - therapeutic use; Viral Core Proteins - metabolism; Virus Assembly - drug effects; Virus Replication - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.12.047

Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies. [Display omitted] •Validation and optimization of an ATDC analogue as a CAE hit.•SAR from a μM hit led to 6 CAEs active at nM.•SPR led to improved metabolic stability and oral bioavailability.•Molecular modeling study revealed a binding mode.•The best CAEs from this series are better than reported CAEs.