- Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands
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Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT1A receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT1A Ki = 8–87 nM; SERT Ki = 8–52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) showed their selectivity towards 5-HT1A receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT1A receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT1A-R and SERT) compared to the precursors.
- ?lifirski, Grzegorz,Król, Marek,Kleps, Jerzy,Podsadni, Piotr,Belka, Mariusz,B?czek, Tomasz,Siwek, Agata,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Bojarski, Andrzej,Kozio?, Anna E.,Tur?o, Jadwiga,Herold, Franciszek
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p. 383 - 397
(2019/07/19)
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- Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824)
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Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating hERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.
- Cho, Young Shin,Whitehead, Lewis,Li, Jianke,Chen, Christine H.-T.,Jiang, Lei,V?gtle, Markus,Francotte, Eric,Richert, Paul,Wagner, Trixie,Traebert, Martin,Lu, Qiang,Cao, Xueying,Dumotier, Berengere,Fejzo, Jasna,Rajan, Srinivasan,Wang, Ping,Yan-Neale, Yan,Shao, Wenlin,Atadja, Peter,Shultz, Michael
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experimental part
p. 2952 - 2963
(2010/08/06)
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- 4-SUBSTITUTED 1-AMINOCYCLOHEXANE DERIVATIVES FOR UTILIZATION AS ORL1-RECEPTOR AND MU-OPIATE RECEPTOR LIGANDS
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The invention relates to 4-substituted 1-aminocyclohexane derivatives of general formula (I), to a method for the production thereof, to medicaments containing said compounds and to the utilization of 4-substituted 1-aminocyclohexane derivatives for the production of medicaments.
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- Heterocyclylindazole and -azaindazole compounds as 5-hydroxytryptamine-6 ligands
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The present invention provides a compound of formula I and the use thereof in the therapeutic treatment of disorders related to or affected by the 5-HT6 receptor.
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- Synthesis of new bridged tetrahydro-β-carbolines and spiro-fused quinuclidines
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Two series of chemically related, conformationally restricted ring systems were synthesized. Bridged tetrahydro-β-carbolines, designed as selective 5-HT receptor ligands, were formed via Pictet-Spengler condensation of cyclic tryptamine precursors. Oxidation of the indole 2-position of the precursors followed by condensation with aldehydes produced spiro-cyclic quinuclidines, containing important muscarine receptor pharmacophores.
- Burm, Brigitte E.A,Gremmen, Christiaan,Wanner, Martin J,Koomen, Gerrit-Jan
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p. 2039 - 2049
(2007/10/03)
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- The synthesis of new heterocyclic bridged ring systems. Analogs of tetrahydro-β-carbolines
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New bridged β-carbolines were synthesized via a short synthetic route. The key step of the sequence is a Pictet-Spengler condensation under neutral conditions, employing a cyclic amine and several aldehydes. Using 5,5-diethoxypentanal gave a bridged analo
- Gremmen, Christiaan,Burm, Brigitte E.A.,Wanner, Martin J.,Koomen, Gerrit-Jan
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p. 1441 - 1444
(2007/10/03)
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