Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA).

The first large scale analysis of in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) data shared across multiple major pharma has been performed. Using advanced matched molecular pair analysis (MMPA), we combined data from three pharmaceutical companies and generated ADMET rules, avoiding the need to disclose the full chemical structures. On top of the very large exchange of knowledge, all companies involved synergistically gained approximately 20% more rules from the shared transformations. There is good quantitative agreement between the rules based on shared data compared to both individual companies' rules and rules published in the literature. Known correlations between log D, solubility, in vitro clearance, and plasma protein binding also hold in transformation space, but there are also interesting exceptions. Data pools such as this allow focusing on particular functional groups and characterizing their ADMET profile. Finally the role of a corpus of robustly tested medicinal chemistry knowledge in the training of medicinal chemistry is discussed

Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization

Discovery of a series of 2-(pyridinyl) pyrimidines as potent antagonists of GPR40

A series of 2-(pyridinyl)pyrimidines were identified as potent GPR40 antagonists. Despite significant challenges related to improving the combination of potency and lipophilicity within the series, the compounds were optimised to identify a suitable in vivo probe compound, which was confirmed to exhibit pharmacology consistent with GPR40 antagonism

An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.

A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics

Tunnelman luominen tanssiteoksen ilmeeseen

Opinnäytetyön teemana ovat lapsuuden painajaiset. Kyseessä on taiteellinen produk-tio, joka tarkastelee painajaisten, katoamisen ja näkymisen teemaa liikekielen, kuvan ja typografian keinoin. Usean kuukauden kestänyt projekti edellytti syvää paneutumista aiheeseen. Työ on saanut vaikutteita musiikin, kirjallisuuden ja elokuvateollisuuden kauhugenrestä. Opinnäytetyön tutkielma käsittelee tunnelman luomista tanssiteoksen ilmeessä. Kirjal-linen osio jakautuu kahteen päälukuun: tanssiteoksen visuaaliseen ilmeeseen ja esityk-seen. Graafiseen ilmeeseen lukeutuvat juliste, käsiohjelma, kutsukortti, notaatio ja In-ternet-sivut. Tanssiteoksen suunnitteluun kuuluvat koreografia, lavastus, puvustus ja äänisuunnittelu. Teoksen tekniseen toteutukseen on saatu apua Kymenlaakson ammat-tikorkeakoulun audiovisuaalisen ilmaisun opiskelijoilta. Työn tarkoituksena oli päästä eroon pimeän peloista ja öisin mielikuviin ilmestyvistä mustista hahmoista. Tutkimukseen on kerätty materiaalia lukemalla kirjallisuutta, haastattelemalla ihmisiä, tutustumalla kauhugenreen ja syventymällä omiin painajaiskokemuksiin. Inspiraation lähteinä ovat erityisesti olleet lähiympäristössä tapahtuneet yliluonnolliset ilmiöt ja kauhutarinat. Lopputuloksena tunnelma ei korostunut ainoastaan konkreettisesti vaan myös aineet-tomasti. Prosessin seurauksena tanssiteokseen syntyi sekä fyysinen tila, jossa kauhu nähtiin, että henkinen tila, jossa kauhu aistittiin. Unien pelkotilat ja pimeässä muodos-tuneet hahmot alkoivat vähitellen kadota, kun turtuminen kauhumaailmaan sai otteen.To begin with, the thesis was inspired by fear. In other words, the theme of the thesis was based on childhood nightmares and traumatic memories. All the words, sentences and images have arisen after two months of paranormal research. The thesis was divided into two parts: the visual identity of the contemporary dance show and the dance performance. A poster, a brochure, an invitation card, a notation and an Internet website were included in the visual identity. Theatrical elements, such as choreography, staging, costumes and sound design were included in the dance per-formance. However, the thesis focuses on describing the atmosphere in the visualiza-tion of the dance performance. The main goal of the process was to release the sensi-tive mind and to get rid of the fear of darkness and imaginary creatures. The material for the thesis was collected by reading literature, interviewing people, experiencing dreams and getting absorbed in the horror genre. The performance was inspired by ghost stories and supernatural phenomena in a real life. The atmosphere highlighted not only in a physical but also in a mental way. Eventu-ally, instead of only one stage, two scenes arose as a result of the process. The first one was regarded as a physical scene where horror was seen. The second one was considered a mental scene where the images of nightmare stemmed from. The fear of darkness alleviated due to the examination of the theme and becoming numb for the genre. Little by little, imaginary creatures came to be regarded as insignificant

Catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoester-derived carbonyl ylides with alkene dipolarophiles

Catalyzed cascade reactions that generate molecular complexity rapidly and in an enantioselective manner are attractive methods for asymmetric synthesis. In the present article, chiral rhodium catalysts are shown to effect such a transformation by using a range of 2-diazo-3,6-diketoesters with bicyclo[2.2.1]alkenes and styrenes as reaction partners. The reactions are likely to proceed by formation of a catalyst-complexed carbonyl ylide from the diazo compound, followed by intermolecular cycloaddition with the alkene dipolarophile. It was possible to obtain high levels of asymmetric induction [up to 89% enantiomeric excess (ee) and 92% ee for the two chiral catalysts investigated]. Enantioselectivity is not highly sensitive to substituent variation at the ketone that forms the ylide; however, branching does improve ee. Observations of dipolarophile-dependent enantiofacial selectivity in the cycloadditions indicate that the dipolarophile can be intimately involved in the enantiodiscrimination process