Xibenolol Hydrochloride

A series of unreported novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring were synthesized, and their antiviral activities were evaluated against tomato spotted wilt virus (TSWV). A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was established, and compound D32 was designed and synthesized according to the analysis results of the CoMFA and CoMSIA models. The bioassay results showed that compound D32 exhibited excellent inactivation activity against TSWV, with EC₅₀ values of 144 μg/mL, which was better than those of ningnanmycin (149 μg/mL) and the lead compound xiangcaoliusuobingmi (525 μg/mL). The binding ability of compound D32 to TSWV CP was tested by microscale thermophoresis (MST), and the binding constant value was 4.4 μM, which was better than those of ningnanmycin (6.2 μM) and xiangcaoliusuobingmi (59.1 μM). Therefore, this study indicates that novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring may be applied as new antiviral agents.

S1P₁ (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction in the number of circulating blood lymphocytes. We hypothesized that S1P₁ receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P₁ receptor modulator library was screened for compounds with clear potency differences in β-arrestin recruitment and G protein alpha i subunit (G _αi) protein-mediated signaling. We describe here the structure-activity relationships of highly potent S1P₁ modulators with apparent pathway selectivity for β-arrestin recruitment. The most differentiated compound, D3-2, displayed a 180-fold higher potency in the β-arrestin recruitment assay (EC₅₀ 0.9 nM) compared with the G _αi-activation assay (167 nM), whereas ponesimod, a S1P₁ modulator that is currently in advanced clinical development in multiple sclerosis, was equipotent in both assays (EC₅₀ 1.5 and 1.1 nM, respectively). Using these novel compounds as pharmacological tools, we showed that although a high potency in β-arrestin recruitment is required to fully internalize S1P₁ receptors, the potency in inducing G _αi signaling determines the rate of receptor internalization in vitro. In contrast to ponesimod, the compound D3-2 did not reduce the number or circulating lymphocytes in rats despite high plasma exposures. Thus, for rapid and maximal S1P₁ receptor internalization a high potency in both G _αi signaling and β-arrestin recruitment is mandatory and this translates into efficient reduction of the number of circulating lymphocytes in vivo.