Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.

Generation and deposition of the amyloid b (Ab) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and c-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Ab, is an attractive therapeutic approach for the treatment of Alzheimer's disease. We have designed a selective non-peptidic BACE-1 inhibitor, GSK188909, that potently inhibits b-cleavage of APP and reduces levels of secreted and intracellular Ab in SHSY5Y cells expressing APP. In addition, we demonstrate that this compound can effectively lower brain Ab in vivo. In APP transgenic mice, acute oral administration of GSK188909 in the presence of a p-glycoprotein inhibitor to markedly enhance the exposure of GSK188909 in the brain decreases b-cleavage of APP and results in a significant reduction in the level of Ab40 and Ab42 in the brain. Encouragingly, subchronic dosing of GSK188909 in the absence of a p-glycoprotein inhibitor also lowers brain Ab. This pivotal first report of central Ab lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease.

Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.

p-met hoxy p hen y I ) t el I u r i u m D iacet at e, p -0 x 0 = b is [ d i p hen y I t r if 1 u or0 -acetoxytellurium] Hydrate, and [ Bis(trif luoroacetoxy)iodo] benzene tThe crystal and molecular structures of the title compounds have been determined from diffractometer data by the heavy-atom method, and their preparations are described. Crystals of (p-MeOC6H4)2Te(02CMe)2 (1 ) are monoclinic, space group P2, fc, with unit-cell dimensions a = 9.529(2), b = 11.984(2), c = 17.035(2) A, p = lOl.i0(2)", 2 = 4, and for 3 033 observed reflections [ l / o ( l ) > 3.01, R = 0.022. Crystals of ([Ph2Te(02CCF3)]20)2*H20 (2) are triclinic, space group P7, with unit-cell dimensions a = 13.988 (3), b = 14.287(3), c = 15.689(3) A, cc = 80.40(2), 6 = 81.89(2), y = 86.65(2)", Z = 2, and for 5 290 observed reflections, R = 0.042.a Crystals of Phl(02CCF3)2 (3) are triclinic, space group P i , with unit-cell dimensions a = 9.787(4), b = 9.055(3), c = 7.674(3) A, a = 91.45(3), p = 99.78(3), y = 89.21 (3)", Z = 2, and for 2 104 observed reflections, R = 0.037. All three compounds have pseudo-trigonalbipyramidal primary geometry [Te-C 2.098(3) and 2.1 03(4), I-C 2.074(4) ; Te-O(p-0x0) 1.981 (7), Te-0 and 1-0 (oxy-anion) 2.1 38-2.352 A], and form secondary bonds to give pentagonal planar systems around Te and I, also with linear C-Te 0 systems. In the light of these results, previously published tellurium nitrate structures are re-interpreted.We have previously examined the intra-and inter-molecular bonding in phenyliodine acetate, dichloroacetate, and nitrate,, and in several phenyltellurium nitrate^.^ These have revealed a diversity of bonding patterns, markedly more complex than those found in the corresponding haiides.'~~ Both series of oxy-salts include an alternation between 'neutral* salts, e.g. PhI(02CMe), and PhZTe(ON02),, and p-0x0-salts, e.g. PhI(ON0,)-0-I(ON0,)Ph. For the iodine compounds, a pattern has also been recognised of 'pentagonal planar' co-ordination, combining the T-shaped geometry expected for iodine(1n) with two secondary I 0 bonds, e.g. structure (A). Nothing similar has yet been recognised in the tellurium compounds. In this paper, additional evidence is brought to bear, from the structures of an aryltellurium acetate and trifluoroacetates of both tellurium and iodine. ExperimentalPreparations.---(p-MeOC6H4),Te(02C Me)2, Compound ( 1 ). Tellurium tetrachloride (27 g, 0.1 mol) was dissolved in a slight excess of anisole (25 cm3, 0.23 m~l ) .~The yellow solution soon became orange and HCI was evolved [reaction (i)]. The solution was then gradually warmed (3 h) to about 100°C until HCI evolution ceased and a solid red-brown mass of the crude product remained. This was recrystallised several times from methanol in the presence of charcoal, until colourless crystals of (p-MeOC6H4)27ieClz were obtained. This compound (0.41 g, 1 mmol) was then dissolved in benzene and AgOzCMe added (0.35 g, 2.1 mmol). The mixture was stirred under reflux for 3 h, filtered, and evaporated slowly to give large crystals of (p-MeOC6H4)2...

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BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.

The findings from this study will inform the label and will contribute to the understanding of the clinical pharmacology of selumetinib. ClinicalTrials.gov identifier: NCT01931761.

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