Eur J Med Chem. 2018 Dec 21;164:179-192. doi: 10.1016/j.ejmech.2018.12.047. [Epub ahead of print]
5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors.
Tang J1, Huber AD2, Pineda DL3, Boschert KN4, Wolf JJ5, Kankanala J1, Xie J1, Sarafianos SG6, Wang Z7.
Author information
1
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
2
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA; Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA.
3
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA; Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA.
4
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211, USA.
5
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA; Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO, 65211, USA.
6
Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA; Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA; Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, MO, 65211, USA.
7
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: [email protected].
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 (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.
1
美国明尼苏达州明尼阿波利斯市明尼苏达大学药学院药物设计中心，55455，美国。
2
Christopher S. Bond生命科学中心，密苏里大学，哥伦比亚，密苏里州，65211，美国;美国密苏里大学兽医学院兽医病理学系，美国密苏里州，65211，美国。
3
Christopher S. Bond生命科学中心，密苏里大学，哥伦比亚，密苏里州，65211，美国;密苏里大学生物化学系，哥伦比亚，密苏里州，65211，美国。
4
Christopher S. Bond生命科学中心，密苏里大学，哥伦比亚，密苏里州，65211，美国;美国密苏里大学营养与运动生理学系，美国密苏里州，65211，美国。
五
Christopher S. Bond生命科学中心，密苏里大学，哥伦比亚，密苏里州，65211，美国;美国密苏里大学医学院分子微生物学与免疫学系，美国密苏里州，65211，美国。
6
Christopher S. Bond生命科学中心，密苏里大学，哥伦比亚，密苏里州，65211，美国;密苏里大学生物化学系，哥伦比亚，密苏里州，65211，美国;美国密苏里大学医学院分子微生物学与免疫学系，美国密苏里州，65211，美国。
7
美国明尼苏达州明尼阿波利斯市明尼苏达大学药学院药物设计中心，55455，美国。电子地址：[email protected]。