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ABSTRACT:We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC 50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.

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We have investigated the effects of prenatal ethanol exposure on GABA(B) receptors (GABA(B)Rs), protein kinase A (PKA), and DA D(1) receptor (DAD(1)R) expressions. GABA(B1)R and GABA(B2)R showed different age-dependent expressions in in vivo fetal rat forebrain from gestational days (GD) 15.5 to 21.5 upon 10% ethanol treatment to mother, with and without baclofen at a dose of 10 mg/kg body weight/day. The protein level changes could not be attributed to changes in the level of transcription since GABA(B)R mRNA presented different expression patterns upon in vivo ethanol treatment. Using in vitro cultivated cortical neurons from GD 17.5 fetuses, we also explored the modulatory effects of ethanol on PKA and DAD(1)R through GABA(B)Rs, under 50 microM baclofen and 100 microM phaclofen administrations, with or without 100 mM of ethanol treatment in the culture media. The results showed that 20 min ethanol treatment without baclofen or phaclofen had increasing effects on both the GABA(B)Rs. Further, baclofen and phaclofen administration significantly affected PKA and GABA(B)R levels upon 20 min and 1 h ethanol treatment. In contrast, DAD(1)R showed increasing effects upon ethanol treatment, which was modulated by GABA(B)R's agonist baclofen and antagonist phaclofen. Therefore the present study suggested that the GABA(B)R activity could modulate ethanol's cellular effects, which possibly including PKA and DAD(1)R activities, and may be an underlying cause of ethanol's effects.