Rombouts F.J.R.,Neuroscience Medicinal Chemistry |
Tresadern G.,Discovery science |
Buijnsters P.,Neuroscience Medicinal Chemistry |
Langlois X.,Janssen Pharmaceutical |
And 6 more authors.
ACS Medicinal Chemistry Letters
A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. © 2015 American Chemical Society. Source
News Article | December 23, 2015
Discovery science led by the University of Alberta's Faculty of Medicine & Dentistry is opening a window on cell biology rarely seen before. New research featured in the Journal of Cell Biology has revealed a real-time look at how genetic information travels within a living cell.
Georgsson J.,CVMD Medicinal Chemistry |
Bergstrom F.,CVMD DMPK |
Nordqvist A.,CVMD Medicinal Chemistry |
Watson M.J.,C4X Discovery |
And 12 more authors.
Journal of Medicinal Chemistry
GPR103, a G-protein coupled receptor, has been reported to have orexigenic properties through activation by the endogenous neuropeptide ligands QRFP26 and QRFP43. Recognizing that central administration of QRFP26 and QRFP43 increases high fat food intake in rats, we decided to investigate if antagonists of GPR103 could play a role in managing feeding behaviors. Here we present the development of a new series of pyrrolo[2,3-c]pyridines as GPR103 small molecule antagonists with GPR103 affinity, drug metabolism and pharmacokinetics and safety parameters suitable for drug development. In a preclinical obesity model measuring food intake, the anorexigenic effect of a pyrrolo[2,3-c]pyridine GPR103 antagonist was demonstrated. In addition, the dynamic 3D solution structure of the C-terminal heptapeptide of the endogenous agonist QRFP26 (20-26) was determined using NMR. The synthetic pyrrolo[2,3-c] pyridine antagonists were compared to this experimental structure, which displayed a possible overlay of pharmacophore features supportive for further design of GPR103 antagonists. © 2014 American Chemical Society. Source
Douthwaite J.A.,Med Immune Ltd. |
Sridharan S.,Med Immune Ltd. |
Huntington C.,Med Immune Ltd. |
Hammersley J.,Med Immune Ltd. |
And 11 more authors.
Therapeutic monoclonal antibodies targeting G-protein-coupled receptors (GPCRs) are desirable for intervention in a wide range of disease processes. The discovery of such antibodies is challenging due to a lack of stability of many GPCRs as purified proteins. We describe here the generation of Fpro0165, a human anti-formyl peptide receptor 1 (FPR1) antibody generated by variable domain engineering of an antibody derived by immunization of transgenic mice expressing human variable region genes. Antibody isolation and subsequent engineering of affi nity, potency and species cross-reactivity using phage display were achieved using FPR1 expressed on HEK cells for immunization and selection, along with calcium release cellular assays for antibody screening. Fpro0165 shows full neutralization of formyl peptide-mediated activation of primary human neutrophils. A crystal structure of the Fpro0165 Fab shows a long, protruding VH CDR3 of 24 amino acids and in silico docking with a homology model of FPR1 suggests that this long VH CDR3 is critical to the predicted binding mode of the antibody. Antibody mutation studies identify the apex of the long VH CDR3 as key to mediating the species cross-reactivity profile of the antibody. This study illustrates an approach for antibody discovery and affinity engineering to typically intractable membrane proteins such as GPCRs. © Julie A Douthwaite, Sudharsan Sridharan, Catherine Huntington, Jayne Hammersley, Rose Marwood, Jonna K Hakulinen, Margareta Ek, Tove Sjögren, David Rider, Cyril Privezentzev, Jonathan C Seaman, Peter Cariuk, Vikki Knights, Joyce Young, Trevor Wilkinson, Matthew Sleeman, Donna K Finch, David C Lowe, and Tristan J Vaughan. Source
Lubin A.,Discovery science |
Geerinckx S.,Discovery science |
Bajic S.,Waters Corporation |
Cabooter D.,Catholic University of Leuven |
And 3 more authors.
Journal of Chromatography A
Eicosanoids, including prostaglandins and thromboxanes are lipid mediators synthetized from polyunsaturated fatty acids. They play an important role in cell signaling and are often reported as inflammatory markers. LC-MS/MS is the technique of choice for the analysis of these compounds, often in combination with advanced sample preparation techniques.Here we report a head to head comparison between an electrospray ionization source (ESI) and a new atmospheric pressure ionization source (UniSpray). The performance of both interfaces was evaluated in various matrices such as human plasma, pig colon and mouse colon. The UniSpray source shows an increase in method sensitivity up to a factor 5. Equivalent to better linearity and repeatability on various matrices as well as an increase in signal intensity were observed in comparison to ESI. © 2016 Elsevier B.V. Source