5-Aminothiophene-2,4-dicarboxamide Analogues As Hepatitis B Virus Capsid Assembly Effectors

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2018 Dec 31

PMID 30594676

Citations 6

Authors

Jing Tang

Andrew D Huber

Dallas L Pineda

Kelsey N Boschert

Jennifer J Wolf

Jayakanth Kankanala

Jiashu Xie

Stefan G Sarafianos

Zhengqiang Wang

Affiliations

Soon will be listed here.

Abstract

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 (EC = 0.11 μM, CC > 100 μM, F = 25%) and 19k (EC = 0.31 μM, CC > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7-10 used in our studies.

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References

Chan S, Wong V, Qin S, Chan H . Infection and Cancer: The Case of Hepatitis B. J Clin Oncol. 2015; 34(1):83-90. DOI: 10.1200/JCO.2015.61.5724. View

Katen S, Chirapu S, Finn M, Zlotnick A . Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators. ACS Chem Biol. 2010; 5(12):1125-36. PMC: 3003741. DOI: 10.1021/cb100275b. View

Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W . Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013; 27(3):221-34. DOI: 10.1007/s10822-013-9644-8. View

Wang J, Ma K, Han M, Guo W, Huang J, Yang D . Nucleoside analogs prevent disease progression in HBV-related acute-on-chronic liver failure: validation of the TPPM model. Hepatol Int. 2015; 8(1):64-71. DOI: 10.1007/s12072-013-9485-5. View

Friesner R, Murphy R, Repasky M, Frye L, Greenwood J, Halgren T . Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006; 49(21):6177-96. DOI: 10.1021/jm051256o. View

Qiu Z, Lin X, Zhang W, Zhou M, Guo L, Kocer B . Discovery and Pre-Clinical Characterization of Third-Generation 4-H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors. J Med Chem. 2017; 60(8):3352-3371. DOI: 10.1021/acs.jmedchem.7b00083. View

Yang L, Shi L, Chen H, Tong X, Wang G, Zhang Y . Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation. Acta Pharmacol Sin. 2014; 35(3):410-8. PMC: 4647886. DOI: 10.1038/aps.2013.175. View

Sari O, Boucle S, Cox B, Ozturk T, Russell O, Bassit L . Synthesis of sulfamoylbenzamide derivatives as HBV capsid assembly effector. Eur J Med Chem. 2017; 138:407-421. PMC: 5581232. DOI: 10.1016/j.ejmech.2017.06.062. View

Qiu Z, Lin X, Zhou M, Liu Y, Zhu W, Chen W . Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors. J Med Chem. 2016; 59(16):7651-66. DOI: 10.1021/acs.jmedchem.6b00879. View

10.

Huber A, Michailidis E, Tang J, Puray-Chavez M, Boftsi M, Wolf J . 3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H. Antimicrob Agents Chemother. 2017; 61(6). PMC: 5444124. DOI: 10.1128/AAC.00245-17. View

11.

Bourne C, Finn M, Zlotnick A . Global structural changes in hepatitis B virus capsids induced by the assembly effector HAP1. J Virol. 2006; 80(22):11055-61. PMC: 1642186. DOI: 10.1128/JVI.00933-06. View

12.

Wu G, Liu B, Zhang Y, Li J, Arzumanyan A, Clayton M . Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly. Antimicrob Agents Chemother. 2013; 57(11):5344-54. PMC: 3811253. DOI: 10.1128/AAC.01091-13. View

13.

Bogolubsky A, Ryabukhin S, Plaskon A, Stetsenko S, Volochnyuk D, Tolmachev A . Dry HCl in parallel synthesis of fused pyrimidin-4-ones. J Comb Chem. 2008; 10(6):858-62. DOI: 10.1021/cc800074t. View

14.

Pantoliano M, Petrella E, Kwasnoski J, Lobanov V, Myslik J, Graf E . High-density miniaturized thermal shift assays as a general strategy for drug discovery. J Biomol Screen. 2002; 6(6):429-40. DOI: 10.1177/108705710100600609. View

15.

Hubatsch I, Ragnarsson E, Artursson P . Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc. 2007; 2(9):2111-9. DOI: 10.1038/nprot.2007.303. View

16.

Tang H, Griffin J, Innaimo S, Lehman-McKeeman L, Llamoso C . The Discovery and Development of a Potent Antiviral Drug, Entecavir, for the Treatment of Chronic Hepatitis B. J Clin Transl Hepatol. 2015; 1(1):51-8. PMC: 4521267. DOI: 10.14218/JCTH.2013.00006. View

17.

Durantel D, Zoulim F . New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus. J Hepatol. 2016; 64(1 Suppl):S117-S131. DOI: 10.1016/j.jhep.2016.02.016. View

18.

Huber A, Wolf J, Liu D, Gres A, Tang J, Boschert K . The Heteroaryldihydropyrimidine Bay 38-7690 Induces Hepatitis B Virus Core Protein Aggregates Associated with Promyelocytic Leukemia Nuclear Bodies in Infected Cells. mSphere. 2018; 3(2). PMC: 5907649. DOI: 10.1128/mSphereDirect.00131-18. View

19.

Weber O, Schlemmer K, Hartmann E, Hagelschuer I, Paessens A, GRAEF E . Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antiviral Res. 2002; 54(2):69-78. DOI: 10.1016/s0166-3542(01)00216-9. View

20.

Stray S, Johnson J, Kopek B, Zlotnick A . An in vitro fluorescence screen to identify antivirals that disrupt hepatitis B virus capsid assembly. Nat Biotechnol. 2006; 24(3):358-62. DOI: 10.1038/nbt1187. View