Thiophene bioisosteres of GluN2B selective NMDA receptor antagonists: Synthesis and pharmacological evaluation of [7]annuleno[b]thiophen-6-amines |
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| Affiliation: | 1. Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany;2. Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-Universität Münster, Germany;1. Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India;2. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India;1. Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China;2. University of Chinese Academy of Sciences, Beijing 100043, PR China;1. Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China;2. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany;3. PET Center, Huashan Hospital, Fudan University, Shanghai 200040, China;4. Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China;5. Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA;1. Drug Metabolism and Pharmacokinetics, Biopharmaceutical Assessment Core Function Unit, Eisai Co., Ltd., 1-3, 5-chome, Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan;2. Bioanalysis Unit, Tsukuba R&D Supporting Division, Sunplanet Co., Ltd., 1-3, 5-chome, Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan;1. Department of Medicinal Chemistry, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada;2. Department of Lead Discovery, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada;3. Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada;4. Celgene Inc., 4550 Towne Centre Court, San Diego, CA 92121, United States |
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| Abstract: | Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: Ki = 5.9 nM; 11d: Ki = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: Ki = 5.9 nM; 11c: Ki = 6.0; 12c: Ki = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ2 affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ1 and σ2 receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5–2-fold) as well as for bromo derivative 18c (≈3-fold). |
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| Keywords: | NMDA receptor GluN2B subunit Selective GluN2B antagonists Negative allosteric modulators Ifenprodil binding site Thiophene bioisosteres Hydroxymethyl derivatives Structure affinity relationships, σ receptor affinity Receptor selectivity |
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