2. Academic Validation
  3. 4-Oxooctahydroquinoline-1(2H)-carboxamides as hepatitis B virus (HBV) capsid core protein assembly modulators

4-Oxooctahydroquinoline-1(2H)-carboxamides as hepatitis B virus (HBV) capsid core protein assembly modulators

  • Bioorg Med Chem Lett. 2022 Feb 15;58:128518. doi: 10.1016/j.bmcl.2021.128518.
Nicky Hwang 1,  Haiqun Ban 2,  Shuo Wu 1,  Kelly McGuire 3,  Ellen Hernandez 4,  Junjun Chen 1,  Qiong Zhao 1,  Manasa Suresh 5,  Benjamin Blass 6,  Usha Viswanathan 1,  John Kulp 1,  Jinhong Chang 1,  Jason Clement 1,  Stephan Menne 5,  Ju-Tao Guo 7,  Yanming Du 8
Affiliations

Affiliations

  • 1 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA.
  • 2 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA; Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Pudong New District, Shanghai 200127, China.
  • 3 Temple University, 1801 N Broad St, Philadelphia, PA 191222, USA.
  • 4 Delaware Valley University, 700 E Butler Ave, Doylestown, PA 18901, USA.
  • 5 Georgetown University Medical Center, 3900 Reservoir Road, Washington, DC 20057, USA.
  • 6 Temple University School of Pharmacy, Department of Pharmaceutical Sciences 3307 North Broad Street, Philadelphia, PA 19140, USA.
  • 7 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA. Electronic address: [email protected].
  • 8 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA. Electronic address: [email protected].
PMID: 34979256 DOI: 10.1016/j.bmcl.2021.128518
Abstract

Hepatitis B virus (HBV) core protein, the building block of the HBV capsid, plays multiple roles in viral replication, and is an attractive target for development of Antiviral agents with a new mechanism of action. In addition to the heteroaryldihydropyrimidines (HAPs), sulfamoylbenzamides (SBAs), dibenzothiazepine derivatives (DBTs), and sulfamoylpyrrolamides (SPAs) that inhibit HBV replication by modulation of viral capsid assembly and are currently under clinical trials for the treatment of chronic hepatitis B (CHB), other chemical structures with activity to modulate HBV capsid assembly have also been explored. Here we describe our continued optimization of a benzamide originating from our high throughput screening. A new bicyclic carboxamide lead featuring an electron deficient non-planar core structure was discovered. Evaluations of its ADMET (absorption, distribution, metabolism, excretion and toxicity) and pharmacokinetic (PK) profiles demonstrate improved metabolic stability and good bioavailability.

Keywords

4-Oxooctahydroquinoline-1(2H)-carboxamides; Capsid assembly modulators; Hepatitis B virus; Phenyl ureas.

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