Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.
Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
Three-dimensional magnetohydrodynamics (MHD) numerical simulation is an important tool in the prediction of solar wind parameters. In this study, we improve our corona interplanetary total variation diminishing MHD model by using a new boundary applicable to all phases of solar cycles. This model uses synoptic magnetogram maps from the Global Oscillation Network Group as the input data. The empirical Wang–Sheeley–Arge relation is used to assign solar wind speed at the lower boundary, while temperature is specified accordingly based on its empirical relation with the solar wind speed. Magnetic field intensity and solar wind density at the boundary are obtained from observational data in the immediate past Carrington rotations, permitting the persistence of these two parameters in a short time period. The boundary conditions depend on only five tunable parameters when simulating the solar wind for different phases of the solar cycle. We apply this model to simulate the background solar wind from 2007 to 2017 and compare the modeled results with the observational data in the OMNI database. Visual inspection shows that our model can capture the time patterns of solar wind parameters well at most times. Statistical analysis shows that the simulated solar wind parameters are all in good agreement with the observations. This study demonstrates that the improved interplanetary total variation diminishing model can be used for predicting all solar wind parameters near the Earth.
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