- Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect
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A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT1A/D2/5-HT2A/5-HT6/5-HT7 receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT1A receptors (e.g., 4c Ki = 2.3 nM, 4l Ki = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT1A receptor) exhibited promising affinities for the 5-HT1A/SERT/D2/5-HT6/5-HT7 receptors and showed an antidepressant-like activity in the FST model.
- Wróbel, Martyna Z.,Chodkowski, Andrzej,Herold, Franciszek,Marciniak, Monika,Dawidowski, Maciej,Siwek, Agata,Starowicz, Gabriela,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Belka, Mariusz,B?czek, Tomasz,Sata?a, Grzegorz,Bojarski, Andrzej J.,Tur?o, Jadwiga
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Read Online
- NEW HETEROCYCLIC COMPOUNDS
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The invention provides new heterocyclic compounds having the general formula (IA) wherein A, L, X, Y, m, n, R1 and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.
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Page/Page column 67; 72-73
(2019/06/17)
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- Substituted heterocyclic compounds and application of same to medicines
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The invention relates to substituted heterocyclic compounds and application of the same to medicines and specifically provides the novel substituted heterocyclic compounds or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and preparation methods thereof. The invention also relates to pharmaceutical compositions containing the compounds and application of the compounds or pharmaceutical compositions to treatment of diseases related to 5-HT6 receptors, especially Alzheimer's disease.
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Paragraph 0201; 0211; 0212; 0213; 0214, 0286; 0287-0289
(2017/04/29)
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- Substituted heterocyclic compounds and its application on the medicament (by machine translation)
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The invention relates to substituted heterocyclic compounds and its application on the medicament, in particular to a novel class of substituted heterocyclic compounds or its isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and their method of preparation. The invention also relates to the compounds of the invention pharmaceutical composition, and said compound or pharmaceutical compositions for the treatment5-HT6receptor-related diseases, in particular Alzheimer's disease in the use thereof. (by machine translation)
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Paragraph 0200; 0201; 0202; 0203; 0247; 0248; 0249; 0250
(2017/06/02)
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- Novel 4-aryl-pyrido[1,2-c ]pyrimidines with dual SSRI and 5-HT1A activity. Part 4
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This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 Combining double low line Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested.A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A Combining double low line 12.4 nM; Ki SERT Combining double low line 15.6 nM 8.1; Ki 5-HT1A Combining double low line 5.6 nM; Ki SERT Combining double low line 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.
- Chodkowski, Andrzej,Wróbel, Martyna Z.,Turlo, Jadwiga,Kleps, Jerzy,Siwek, Agata,Nowak, Gabriel,Belka, Mariusz,Baczek, Tomasz,Mazurek, Aleksander P.,Herold, Franciszek
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- Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents. Part 1
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A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated. The chemical structures of the newly prepared compounds were confirmed by 1H NMR, 13C NMR and ESI-HRMS spectra data. All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands. Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT. Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests. Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT 7 and 5-HT2A receptors. In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor. The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists.
- Wróbel, Martyna Z.,Chodkowski, Andrzej,Herold, Franciszek,Gomó?ka, Anna,Kleps, Jerzy,Mazurek, Aleksander P.,Pluciński, Franciszek,Mazurek, Andrzej,Nowak, Gabriel,Siwek, Agata,Stachowicz, Katarzyna,S?awin?ska, Anna,Wolak, Ma?gorzata,Szewczyk, Bernadeta,Sata?a, Grzegorz,Bojarski, Andrzej J.,Tur?o, Jadwiga
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p. 484 - 500
(2013/07/25)
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- 3-PIPERIDIN-4-YL-INDOLE ORL-1 RECEPTOR MODULATORS
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The present invention is directed to novel 3-piperidin-4-yl-indole derivatives of formula (I) and forms thereof, wherein X, R1, R2, R3, R4 and R5 are as herein defined, pharmaceutical compositions thereof and use as ORL-1 receptor modulators for treating, preventing or ameliorating ORL-1 receptor mediated disorders and conditions.
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Page/Page column 37-38
(2008/06/13)
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- Synthesis and structure-activity relationships of novel histamine H 1 antagonists: Indolylpiperidinyl benzoic acid derivatives
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A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H1 antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT2 receptor. Extensive optimization was carried out within this series and a number of histamine H1 antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48, 51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
- Fonquerna, Silvia,Miralpeix, Montse,Pagès, Lluís,Puig, Carles,Cardús, Arantxa,Antón, Francisca,Cárdenas, álvaro,Vilella, Dolors,Aparici, Mónica,Calaf, Elena,Prieto, José,Gras, Jordi,Huerta, Josep M.,Warrellow, Graham,Beleta, Jorge,Ryder, Hamish
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p. 6326 - 6337
(2007/10/03)
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- Indolylpiperidine derivatives as antihistaminic and antiallergic agents
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Indolylpiperidine compounds of formula (I) wherein: A1 represents an alkylene, alkyleneoxy, alkylenethio, alkanoyl or hydroxyalkylene group; A2 represents a single bond, an alkylene or alkenylene group; W represents a single bond or a phenylene or furanylene group which is unsubstituted or substituted by one or more halogen atoms, alkoxy groups and/or alkyl groups; R1 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl alkoxy-alkoxyalkyl, phenylalkyl group wherein the phenyl ring is unsubstituted or substituted by one or more halogen atoms or alkyl, alkoxy or arylalkoxy groups, or a cycloalkylalkyl group wherein the cycloalkyl group is unsubstituted or substituted by one or more halogen atoms, alkyl groups or alkoxy groups; R2 represents a hydrogen or halogen atom or an alkyl or alkoxy group; and R3 represents a carboxyl group or a tetrazolyl group; and pharmaceutically acceptable salts thereof, process for their preparation and medicinal use.
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- 6-SUBSTITUTED-1,2,3,4-TETRAHYDRO-9H-CARBAZOLES AND 7-SUBSTITUTED-10H-CYCLOHEPTA [7,6-B]INDOLES: NEW 5-HT1F AGONISTS
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This invention provides novel 6-substituted-1,2,3,4-tetrahydro-9H-carbazoles and 7-substituted-10H-cyclohepta[7,6-b]indoles. These compounds are 5-HT 1F agonists which are useful for the treatment of migraine and associated disorders.
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- 5-SUBSTITUTED-3-(1,2,3,6-TETRAHYDROPYRIDIN-4-YL)-AND 3-(PIPERIDIN-4-YL)-1H-INDOLES: NEW 5-HT1F AGONISTS
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This invention provides novel 5-HT 1F agonists of Formula I STR1 where A--B, R, R 1 and X are as defined in the specification, which are useful for the treatment of migraine and associated disorders.
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- 3--4--and 3--4-piperidinyl-1h-indoles: new 5-HT1F agonists
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This invention provides novel 5-HT1F agonists which are useful for the treatment of migraine and associated disorders having the following formula: STR1 wherein A, B, X, Y, Ar and n are defined in the specification.
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