JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza. KEYWORDS: Influenza, PB2 subunit, 7-azaindole, aldehyde oxidase, metabolic stability S easonal influenza causes high morbidity and mortality around the globe annually. The impact of influenza epidemics is estimated to be approximately 3.5 million cases for severe illness and 300,000 to 500,000 deaths annually. 1 Transmission of novel strains of influenza from other species (mammals and birds) can cause human pandemics, such as the 2009 H1N1 swine flu pandemic as well as the H5N1 avian flu outbreaks. 2 Influenza is caused by three orthomyxoviridae family viruses, influenza A, B, and C. 3 The current antiviral standard of care (SOC) for treatment of influenza cases in the United States are the neuraminidase inhibitors, oseltamivir 1 (Figure 1) and zanamivir. While these agents can be effective against a variety of type A and B influenza viruses, they suffer from two main limitations. First, the neuraminidase inhibitors have only a moderate impact on the severity of symptoms as well as duration of sickness, and they must be administered within 24−48 h of the infection. 4 Second, resistance to this class of antivirals has generated significant concern, 5 especially with the report that the H5N1 influenza virus has shown resistance to oseltamivir, 6 reinforcing the critical need for new anti-influenza therapeutics with novel mechanisms of action.We have previously reported a series of potent 7-azaindolebased influenza inhibitors, highlighted by JNJ-63623872 (2) (formerly known as VX-787). 7 The molecular target for these compounds was identified as the PB2 subunit of the influenza viral polymerase. The PB2 subunit contains a cap binding domain for 7-methyl GTP (m7-GTP) on the 5′-end of the host pre-mRNA. Once bound to PB2, the polymerase acidic protein (PA) endonuclease subunit cleaves the host RNA strand, leaving a 10−13 nucleotide primer. The PB1 subunit contains the conserved polymerase domain and utilizes the pr...
Purpose -The purpose of this paper is to determine the drivers of economic financial success of US cow-calf operations. Design/methodology/approach -This research uses a system of equations (DuPont analysis) in conjunction with 2008 farm-level data from the US Department of Agriculture's Agricultural Resource Management Survey to evaluate the factors driving cow-calf profitability, namely net profit margins, asset turnover ratio, and asset-to-equity ratio. Findings -The study finds that the main drivers of return on equity are region, number of harvested acres on the farm, diversification of the farm, operator off-farm work, spousal off-farm work, and adoption of technologies. Of these factors, those for which producers can make short-term adjustments include off-farm work decisions and adoption of technologies. Longer-term adjustments can be made for farm diversification. Originality/value -To the authors' knowledge, no existing research has used farm-level data across US production regions to examine the factors affecting returns to equity of US cow-calf operations. These research results may be used to identify strategies producers can use to improve their farm's economic viability, areas where extension services can assist farmers in making better financial decisions and economic factors that are likely to lead to structural changes in the beef industry.
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