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Lucas M.C.,Hoffmann-La Roche | Lucas M.C.,Cubist Pharmaceuticals Inc. | Goldstein D.M.,Hoffmann-La Roche | Goldstein D.M.,Principia BioPharma | And 12 more authors.
Journal of Medicinal Chemistry | Year: 2012

A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field. © 2012 American Chemical Society.

Padilla F.,Hoffmann-La Roche | Bhagirath N.,Hoffmann-La Roche | Chen S.,Hoffmann-La Roche | Chiao E.,Hoffmann-La Roche | And 30 more authors.
Journal of Medicinal Chemistry | Year: 2013

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series. © 2013 American Chemical Society.

Wu G.-L.,Capital Normal University | Wu G.-L.,Bioduro Beijing Co. | Cao S.-L.,Capital Normal University | Chen J.,Bioduro Beijing Co. | Chen Z.,Renmin University of China
European Journal of Organic Chemistry | Year: 2012

A new type of N-heterocyclic carbene bearing ruthenium olefin metathesis catalyst was prepared through the incorporation of a chelated pyrimidinyl methylene subunit, in which electron-rich substituents were attached to stabilize the ruthenium complexes. These catalysts were successfully used in various types of olefin metathesis reactions, including ring-closing metathesis (RCM), cross-metathesis (CM), enyne metathesis (EM), and ring-opening metathesis polymerization (ROMP) reactions. The results therein showed that the presence of an electron-deficient pyrimidine structure greatly enhanced the new NHC ruthenium complexes' catalytic activities. New N-heterocyclic carbene bearing ruthenium olefin metathesis catalysts were synthesized and applied in various types of olefin metathesis reactions, including ring-closing metathesis, cross-metathesis, enyne metathesis, and ring-opening metathesis polymerization reactions. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Deng Y.,Huazhong University of Science and Technology | Deng Y.,Ruhr University Bochum | Zhang W.,Ruhr University Bochum | Zhang W.,Bioduro Beijing Co. | And 5 more authors.
PLoS ONE | Year: 2011

Seven-transmembrane receptors typically mediate olfactory signal transduction by coupling to G-proteins. Although insect odorant receptors have seven transmembrane domains like G-protein coupled receptors, they have an inverted membrane topology, constituting a key difference between the olfactory systems of insects and other animals. While heteromeric insect ORs form ligand-activated non-selective cation channels in recombinant expression systems, the evidence for an involvement of cyclic nucleotides and G-proteins in odor reception is inconsistent. We addressed this question in vivo by analyzing the role of G-proteins in olfactory signaling using electrophysiological recordings. We found that Gαs plays a crucial role for odorant induced signal transduction in OR83b expressing olfactory sensory neurons, but not in neurons expressing CO2 responsive proteins GR21a/GR63a. Moreover, signaling of Drosophila ORs involved Gαs also in a heterologous expression system. In agreement with these observations was the finding that elevated levels of cAMP result in increased firing rates, demonstrating the existence of a cAMP dependent excitatory signaling pathway in the sensory neurons. Together, we provide evidence that Gαs plays a role in the OR mediated signaling cascade in Drosophila. © 2011 Deng et al.

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