Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly.

A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is ß, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC50 values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes.

Esophageal necrosis associated with sodium polystyrene sulfonate (Kayexalate) use.

Acute esophageal necrosis is a rare cause of gastrointestinal bleeding. Endoscopically, it appears as a circumferential black-appearing mucosa affecting almost universally the mid and distal esophagus. Risk factors include low flow states, malnutrition, alcoholism, and the presence of multiple comorbidities. Prolonged exposure to gastric secretions and direct contact with corrosive agents also induce mucosal ischemia. Sodium polystyrene sulfonate use has been associated with severe gastrointestinal adverse events, including increased risk of small bowel and colonic necrosis and perforation. In susceptible individuals, sodium polystyrene sulfonate can also induce esophageal ischemia and necrosis, as illustrated in this case.