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Wyttenbach N.,Small Molecule Research | Janas C.,Small Molecule Research | Janas C.,Goethe University Frankfurt | Siam M.,Small Molecule Research | And 4 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

Purpose: Development of a novel, rapid, miniaturized approach to identify amorphous solid dispersions with maximum supersaturation and solid state stability. Method: Three different miniaturized assays are combined in a 2-step decision process to assess the supersaturation potential and drug-polymer miscibility and stability of amorphous compositions. Step 1: SPADS dissolution assay. Drug dissolution is determined in 96-well plates to detect systems that generate and maintain supersaturation. Promising combinations graduate to step 2. Step 2: SPADS interaction and SPADS imaging assays. FTIR microspectroscopy is used to study intermolecular interactions. Atomic force microscopy is applied to analyze molecular homogeneity and stability. Based on the screening results, selected drug-polymer combinations were also prepared by spray-drying and characterized by classical dissolution tests and a 6-month physical stability study. Results: From the 7 different polymers and 4 drug loads tested, EUDRAGIT® E PO at a drug load of 20% performed best for the model drug CETP(2). The classical dissolution and stability tests confirmed the results from the miniaturized assays. Conclusion: The results demonstrate that the SPADS approach is a useful de-risking tool allowing the rapid, rational, time- and cost-effective identification of polymers and drug loads with appropriate dual function in supersaturation performance and amorphous drug stabilization. © 2013 Elsevier B.V. All rights reserved.


Maeda S.,Paul Scherrer Institute | Maeda S.,ETH Zurich | Sun D.,Paul Scherrer Institute | Sun D.,ETH Zurich | And 12 more authors.
PLoS ONE | Year: 2014

The activation of the G-protein transducin (Gt) by rhodopsin (Rho) has been intensively studied for several decades. It is the best understood example of GPCR activation mechanism and serves as a template for other GPCRs. The structure of the Rho/G protein complex, which is transiently formed during the signaling reaction, is of particular interest. It can help understanding the molecular details of how retinal isomerization leads to the G protein activation, as well as shed some light on how GPCR recognizes its cognate G protein. The native Rho/Gt complex isolated from bovine retina suffers from low stability and loss of the retinal ligand. Recently, we reported that constitutively active mutant of rhodopsin E113Q forms a Rho/Gt complex that is stable in detergent solution. Here, we introduce methods for a large scale preparation of the complex formed by the thermo-stabilized and constitutively active rhodopsin mutant N2C/M257Y/D282C(RhoM257Y) and the native Gt purified from bovine retinas. We demonstrate that the light-activated rhodopsin in this complex contains a covalently bound unprotonated retinal and therefore corresponds to the active metarhodopin II state; that the isolated complex is active and dissociates upon addition of GTP cS; and that the stoichiometry corresponds to a 1:1 molar ratio of rhodopsin to the heterotrimeric G-protein. And finally, we show that the rhodopsin also forms stable complex with Gi. This complex has significantly higher thermostability than RhoM257Y/Gt complex and is resistant to a variety of detergents. Overall, our data suggest that the RhoM257Y/Gi complex is an ideal target for future structural and mechanistic studies of signaling in the visual system. © 2014 Maeda et al.


Qian Y.,Small Molecule Research | Hamilton M.,Small Molecule Research | Sidduri A.,Small Molecule Research | Gabriel S.,Small Molecule Research | And 17 more authors.
Journal of Medicinal Chemistry | Year: 2012

Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF. © 2012 American Chemical Society.


Werner M.,Small Molecule Research | Kuratli C.,Small Molecule Research | Martin R.E.,Small Molecule Research | Hochstrasser R.,Small Molecule Research | And 4 more authors.
Angewandte Chemie - International Edition | Year: 2014

Drug discovery is a multifaceted endeavor encompassing as its core element the generation of structure-activity relationship (SAR) data by repeated chemical synthesis and biological testing of tailored molecules. Herein, we report on the development of a flow-based biochemical assay and its seamless integration into a fully automated system comprising flow chemical synthesis, purification and in-line quantification of compound concentration. This novel synthesis-screening platform enables to obtain SAR data on b-secretase (BACE1) inhibitors at an unprecedented cycle time of only 1 h instead of several days. Full integration and automation of industrial processes have always led to productivity gains and cost reductions, and this work demonstrates how applying these concepts to SAR generation may lead to a more efficient drug discovery process. Ready, steady, go! A flow-compatible dose-response screening assay was developed and seamlessly merged with chemical synthesis and analysis for investigation of structure-activity relationships (SAR) of β-secretase (BACE1) inhibitors. Yielding SAR data at a record-breaking cycle time this integrated platform may be a powerful method for the ever-accelerating drug discovery race. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Banner D.W.,Small Molecule Research | Gsell B.,Small Molecule Research | Benz J.,Small Molecule Research | Bertschinger J.,Covagen Inc. | And 24 more authors.
Acta Crystallographica Section D: Biological Crystallography | Year: 2013

The aspartic protease BACE2 is responsible for the shedding of the transmembrane protein Tmem27 from the surface of pancreatic β-cells, which leads to inactivation of the β-cell proliferating activity of Tmem27. This role of BACE2 in the control of β-cell maintenance suggests BACE2 as a drug target for diabetes. Inhibition of BACE2 has recently been shown to lead to improved control of glucose homeostasis and to increased insulin levels in insulin-resistant mice. BACE2 has 52% sequence identity to the well studied Alzheimer's disease target enzyme β-secretase (BACE1). High-resolution BACE2 structures would contribute significantly to the investigation of this enzyme as either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers to obtain the first high-resolution structures of BACE2. Eight crystal structures in six different packing environments define an ensemble of low-energy conformations available to the enzyme. Here, the different strategies used for raising and selecting BACE2 binders for cocrystallization are described and the crystallization success, crystal quality and the time and resources needed to obtain suitable crystals are compared. © 2013 International Union of Crystallography.


Alzieu T.,Small Molecule Research | Lehmann J.,Small Molecule Research | Naidu A.B.,Simon Fraser University | Martin R.E.,Small Molecule Research | Britton R.,Simon Fraser University
Chemical Communications | Year: 2014

We report the optimization of a neglected reaction for the rapid and direct conversion of oxazoles into N-substituted imidazoles. The utility of this microwave-promoted reaction for diversity-oriented synthesis is demonstrated in the preparation of >40 N-substituted imidazoles, including α-imidazolyl esters. © 2014 The Royal Society of Chemistry.

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