Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

bThe type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 g/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC 90 s against clinical isolates ranged from 0.015 g/ml for Streptococcus pneumoniae to 0.25 g/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 ؋ 10 ؊10 with compound A and <5.8 ؋ 10؊11 with compound B at concentrations equivalent to 8؋ the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.

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F o r m a t i o n o f O x a z o l i d i n o n e s o r A l l y l i c A m i d e s f r o m a C o m m o n P r e c u r s o rAbstract: The use of palladium to effect two different reactions on a common starting material is presented. With a copper oxidant, an aminohalogenation is achieved to produce oxazolidinones. When the copper is absent, a [3,3]-sigmatropic rearrangement takes place to produce allylic amides.The progress of research into organometallic reagents in the last 40 years is perhaps epitomized by looking at the entries for 'palladium' in Synthesis since its inception in 1969. In the 1970s there are a few mentions of palladium -notable mostly as palladium(II) reactions. However, the frequency of articles using the transition metal increases in the 1980s and 1990s, and most dramatically in the late 1990s and 2000s, with a bias towards palladium(0)-mediated processes. There is obviously still an increasing use of transition-metal mediated reactions and, of these, palladium is among the most common. As such, we wish to present our results on two palladium-mediated reactions. Of particular note is the versatility of the catalyst to effect different reactions on the same substrate through judicious choice of reaction conditions. We were initially looking at a means through which to activate alkenes towards functionalisation with heteroatoms, principally oxygen and nitrogen. For the most part, dihydroxylation and aminohydroxylation reactions have been the domain of osmium, but we recently highlighted that there is a complementary role played by palladium in related reactions. 1 Most notable on this front is the recent work by Stahl 2 and Sorensen 3 who have shown that palladium can produce highly functionalised aminohydroxylation products from alkenes. We were keen to look at the use of tethered systems, which would provide a means to control regiochemistry and perhaps also stereochemistry. To this end, we started with systems such as those shown in Scheme 1. Here, we were concerned with the palladium(II)-mediated reaction of carbamates with pendant olefins to produce the corresponding heterocycles. This type of reaction has been achieved by Donohoe 4 with osmium in an aminohydroxylation reaction and, more recently, with palladium by Stahl 2 and Sorenson. 3 We have initially investigated aminohalogenation reactions of tethered systems. Lu 5 and Chemler 6 have reported on this type of reaction, however, both groups utilized tosyl protecting groups on the nitrogen. More recently, Michael has illustrated a related reaction employing a tridentate palladium catalyst. 7 We were keen to avoid the use of tosylate as it can present difficulties in removal, and we were also interested in the possibility of combining several reactions into one pot. We therefore chose the trichloroacetyl group, which appeared to fit the profile of providing the necessary protection and reactivity for the nitrogen, whilst also being relatively straightforward to remove by several different methods. We started by preparing the requisite carba...