A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.

Ball oder Röhre: Flexible und amorphe Nanoröhren bilden sich aus einem Palladiumsalz und einem mehrzähnigen Liganden mit tetraedrischer Struktur (rechts). Dagegen führen Liganden mit zweidimensionaler Geometrie unabhängig von der Zahl der Metallkoordinationsstellen zur Bildung von Kugeln und deren Aggregaten (links).

Macrocyclic compounds represent a structural class with exceptional potential for biological activity; however, they have historically been underrepresented in screening collections and synthetic libraries. In this article we report the development of a highly step-efficient strategy for the diversity-oriented synthesis of complex macrocyclic architectures, using a modular approach based on the two-directional synthesis of bifunctional linear precursors and their subsequent combination in a two-directional macrocyclisation process. In this proof of principle study, the synthesis of 14 such compounds was achieved. Cheminformatic analysis of the compounds produced suggests that they reside in biologically relevant regions of chemical space and the compounds were screened for activity against two cancer cell lines.

Non-invasive delivery of biotherapeutics, as an attractive alternative to injections, could potentially be achieved through the mucosal surfaces, utilizing nanoscale therapeutic carriers. However, nanoparticles do not readily cross the mucosal barriers, with the epithelium presenting a major barrier to their translocation. The transcytotic pathway of vitamin B12 has previously been shown to ‘ferry’ B12-decorated nanoparticles across intestinal epithelial (Caco-2) cells. However, such studies have not been reported for the airway epithelium. Furthermore, the presence in the airways of the cell machinery responsible for transepithelial trafficking of B12 is not widely reported. Using a combination of molecular biology and immunostaining techniques, our work demonstrates that the bronchial cell line, Calu-3, expresses the B12-intrinsic factor receptor, the transcobalamin II receptor and the transcobalamin II carrier protein. Importantly, the work showed that sub-200 nm model nanoparticles chemically conjugated to B12 were internalised and transported across the Calu-3 cell layers, with B12 conjugation not only enhancing cell uptake and transepithelial transport, but also influencing intracellular trafficking. Our work therefore demonstrates that the B12 endocytotic apparatus is not only present in this airway model, but also transports ligand-conjugated nanoparticles across polarised epithelial cells, indicating potential for B12-mediated delivery of nanoscale carriers of biotherapeutics across the airways.

The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.

The sequential intramolecular conjugate addition of the oxime 13 followed by intramolecular dipolar cycloaddition of the intermediate nitrone 14 affords a mixture of the isoxazolidines 15, 16 and 17. The tricyclic 6,5,5-adduct 15 is believed to be the product of kinetic control and can be equilibrated with the epimeric tricyclic 6,5,5-isoxazolidine 17 through a beta-elimination/conjugate addition process. Conditions have been developed for the two-step conversion of the ketone 12 under thermodynamic control into the racemic tricyclic 6,6,5-adduct 16 which is the core precursor of all the known histrionicotoxin alkaloids.

Starting from commercially available ( S)-glycidol, and via a common intermediate, the total synthesis of (-)-histrionicotoxin 285A and (-)-perhydrohistrionicotoxin has been achieved. Key to this synthesis was the efficient construction of a six-membered, chiral, cyclic nitrone.

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