- BENZOXAZINONE DERIVATIVES AND ANALOGUES THEREOF AS MODULATORS OF TNF ACTIVITY
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A series of substituted 3,4-dihydro-2H-.1,4-benzoxazin-3-one derivatives, and analogues thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune
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- The Cu(OTf)2 catalysed microwave assisted synthesis of a new scaffold, 7-aryl-7,8-dihydropyrido[4,3-c]pyridazin-5(6H )-one
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The synthesis of novel 7-aryl-7,8-dihydropyrido[4,3-c]pyridazin-5(6 H)-ones is described including a one-step Mannich-type reaction followed by intramolecular ring closure of ethyl 3-methylpyridazine-4-carboxylate and aldimines, catalysed by the Lewis aci
- Muylaert, Koen,Mangelinckx, Sven,Jatczak, Martyna,De Coen, Laurens M.,Van Hecke, Kristof,Stevens, Christian V.
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p. 139 - 155
(2015/02/19)
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- G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype
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GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-α and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-α and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.
- H?genauer, Klemens,Arista, Luca,Schmiedeberg, Niko,Werner, Gudrun,Jaksche, Herbert,Bouhelal, Rochdi,Nguyen, Deborah G.,Bhat, B. Ganesh,Raad, Layla,Rauld, Celine,Carballido, José M.
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p. 10343 - 10354
(2015/02/19)
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- PYRIDAZINE-, PYRIDINE- AND PYRANE-DERIVATIVES AS GPBAR1 AGONISIS
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A compound of formula (I) wherein the substituents have various meanings, optionally in salt and/or solvate form, and their use as pharmaceuticals.
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- A Novel Approach to the Pyridopyridazine Ring. Synthesis of Pyridopyridazin-5(6H)-one from 3,4-Disubstituted Pyridazines
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The synthesis of new pyridopyridazin-5(6H)-one from ethyl 3-methyl-4-pyridazinecarboxylate using an enamination/ring closure sequence is described.The starting material is easily available from a hetero Diels-Alder reaction between a 1,2-diaza-1,3-
- Vors, Jean-Pierre
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p. 1043 - 1046
(2007/10/02)
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- PYRIDAZINES XXIV. APPLICATION OF RADICALIC ETHOXYCARBONYLATION TO THE SYNTHESIS OF PYRIDAZINE MONO- AND POLYCARBOXYLIC ACID ESTERS
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Reactivity of pyridazines 1, 2, 3, 16 towards ethoxycarbonylradical (generated by redox decomposition of oxyhydroperoxyde of ethylpyruvate) was studied.Application of this type of homolytic substitution for synthesis of hitherto not accessible pyridazine carboxylic acid esters 6, 8, 9, 12, 13, 14, 15, 17 is demonstrated.In addition improved synthesis of diethyl 4,5-pyridazinedicarboxylate (5) is proposed.
- Heinisch, Gottfried,Loetsch, Gerhard
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p. 1199 - 1206
(2007/10/02)
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