- THIOPHENE DERIVATIVES FOR THE TREATMENT OF DISORDERS CAUSED BY IGE
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Thiophene derivatives of formula (I) and a pharmaceutically acceptable salt thereof are provided. These compounds have utility for the treatment or prevention of disorders caused by IgE, such as allergy, type 1 hypersensitivity or familiar sinus inflammation.
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Page/Page column 183
(2020/01/11)
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- A comparative study of fragment screening methods on the p38α kinase: New methods, new insights
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The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets.
- Pollack, Scott J.,Beyer, Kim S.,Lock, Christopher,Mueller, Ilka,Sheppard, David,Lipkin, Mike,Hardick, David,Blurton, Peter,Leonard, Philip M.,Hubbard, Paul A.,Todd, Daniel,Richardson, Christine M.,Ahrens, Thomas,Baader, Manuel,Hafenbradl, Doris O.,Hilyard, Kate,Buerli, Roland W.
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scheme or table
p. 677 - 687
(2012/07/16)
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- Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3
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Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.
- Malerich, Jeremiah P.,Lam, Jennifer S.,Hart, Barry,Fine, Richard M.,Klebansky, Boris,Tanga, Mary J.,D'Andrea, Annalisa
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scheme or table
p. 7454 - 7457
(2011/01/12)
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- INHIBITORS OF DIACYLGLYCEROL O-ACYLTRANSFERASE TYPE 1 ENZYME
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The present invention relates to compounds of formula (I) wherein R1, R3, X, Q, Z, A, D, m, and n are defined herein. Pharmaceutical compositions and methods for treating DGAT-1 related diseases or conditions are also disclosed.
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Page/Page column 68
(2010/11/29)
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- Diphenyl Cyanocarbonimidate. A Versatile Synthon for the Construction of Heterocyclic Systems
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A simple high yield synthesis of diphenyl cyanocarbonimidate is reported.This synthon may be used to prepare functionalized benzimidazoles, benzoxazoles and triazoles in good yield under mild conditions.
- Webb, R. Lee,Labaw, Clifford S.
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p. 1205 - 1206
(2007/10/02)
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