- Synthesis of Conformationally Locked and C-Linked Analogues of Imidazole-Based Ketene Dithioacetal Fungicides
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First examples with the unknown tricyclic 4,8 b -dihydro-3 aH -indeno[1,2- d ][1,3]dithiole ring system have been prepared. Also, imidazoles linked in ring position 5 to a ketene dithioacetal and 1,3-dithiane derivatives with an exocyclic cyano- and imidazole-substituted C-C double bond are completely new. All these compounds are either conformationally locked, C-linked or six-ring analogues of the antifungal agent luliconazole. Synthesis and fungicidal activity of these sterol biosynthesis inhibitors are reported.
- Gagnepain, Julien,Jeanmart, Stephane,Bonvalot, Damien,Jacob, Olivier,Lamberth, Clemens
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- Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na+/H+ Exchanger Type 3 (NHE3)
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The design, synthesis, and structure-activity relationship of 1-phenoxy-2-aminoindanes as inhibitors of the Na+/H+ exchanger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS). The chemical optimization resulted in the discovery of potent, selective, and orally bioavailable NHE3 inhibitors with 13d as best compound, showing high in vitro permeability and lacking CYP2D6 inhibition as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes onto the X-ray structure of 13d then provided 3D-QSAR models for NHE3 inhibition capturing guidelines for optimization. These models showed good correlation coefficients and allowed for activity estimation. In silico ADMET models for Caco-2 permeability and CYP2D6 inhibition were also successfully applied for this series. Moreover, docking into the CYP2D6 X-ray structure provided a reliable alignment for 3D-QSAR models. Finally 13d, renamed as SAR197, was characterized in vitro and by in vivo pharmacokinetic (PK) and pharmacological studies to unveil its potential for reduction of obstructive sleep apneas.
- Rackelmann, Nils,Matter, Hans,Englert, Heinrich,Follmann, Markus,Maier, Thomas,Weston, John,Arndt, Petra,Heyse, Winfried,Mertsch, Katharina,Wirth, Klaus,Bialy, Laurent
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p. 8812 - 8829
(2016/10/22)
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- Indanylidenes. 2. Design and synthesis of (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, a potent antiinflammatory and analgesic agent without centrally acting muscle relaxant activity
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Extension of the structure-activity relationship studies that led to the discovery of the nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro
- Musso, David L.,Orr, G. Faye,Cochran, Felicia R.,Kelley, James L.,Selph, Jeffrey L.,Rigdon, Greg C.,Cooper, Barrett R.,Jones, Michael L.
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p. 409 - 416
(2007/10/03)
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- Polyhalogen-substituted cinnamic acids and cinnamic acid derivatives and a process for the preparation of polyhalogen-substituted cinnamic acids and cinnamic acid derivatives
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Polyhalogenated cinnamic acids and cinnamic acid derivatives are prepared by reacting diazonium salts accessible from polyhalogenated anilines with acrylic acid or acrylic acid derivatives in the presence of a homogeneous, palladium-containing catalyst at about ?5 to about +100° C. Some of the cinnamic acids and cinnamic acid derivatives obtainable in this way are new. Cinnamic acids and cinnamic acid derivatives which can be prepared according to the invention can be used for the preparation of indanones which are precursors for agro- and pharmaceutical chemicals and for substances having liquid-crystalline properties.
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- Quinolones used as MRS inhibitors and bactericides
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Compounds of formula (I) are inhibitors of the bacterial enzymeS aureusmethionyl tRNA synthetase and are of use in treating bacterial infections.
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- Amide derivatives and their therapeutic use
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A compound of formula (I), wherein R1 and R2 are independently selected from chloro, fluoro, bromo, C1-6 alkyl, C1-6 alkoxy or C1-6 haloalkyl provided that both R1 and R2 are not
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