4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity.
| Title: | 4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity. |
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| Authors: | Wágner G; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Mocking TAM; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Arimont M; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Provensi G; Rani B; Silva-Marques B; Department of Physiotherapy , Federal University of São Carlos , Washington Luís, km 235 , SP-310 São Carlos , Brazil.; Latacz G; Department of Technology and Biotechnology of Drugs, Medical College , Jagiellonian University , Medyczna 9 , PL 30-688 Cracow , Poland.; Da Costa Pereira D; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Karatzidou C; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Vischer HF; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Wijtmans M; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Kieć-Kononowicz K; Department of Technology and Biotechnology of Drugs, Medical College , Jagiellonian University , Medyczna 9 , PL 30-688 Cracow , Poland.; de Esch IJP; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Leurs R; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands. |
| Source: | Journal of medicinal chemistry [J Med Chem] 2019 Dec 12; Vol. 62 (23), pp. 10848-10866. Date of Electronic Publication: 2019 Nov 20. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Amines/*chemical synthesis ; Amines/*pharmacology ; Histamine Agonists/*chemical synthesis ; Histamine Agonists/*pharmacology; Amines/chemistry ; Behavior, Animal/drug effects ; Histamine Agonists/chemistry ; Memory/drug effects ; Animals ; HEK293 Cells ; Humans ; Mice ; Molecular Docking Simulation ; Molecular Structure ; Protein Binding ; Protein Conformation ; Social Behavior |
| Abstract: | Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure-activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research. |
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| Substance Nomenclature: | 0 (Amines); 0 (Histamine Agonists) |
| Entry Date(s): | Date Created: 20191102 Date Completed: 20200622 Latest Revision: 20231104 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC6912857 |
| DOI: | 10.1021/acs.jmedchem.9b01462 |
| PMID: | 31675226 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't