4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity

Gábor Wágner, Tamara A.M. Mocking, Marta Arimont, Gustavo Provensi, Barbara Rani, Bruna Silva-Marques, Gniewomir Latacz, Daniel Da Costa Pereira, Christina Karatzidou, Henry F. Vischer, Maikel Wijtmans, Katarzyna Kieć-Kononowicz, Iwan J.P. De Esch, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Number of pages19
JournalJournal of Medicinal Chemistry
DOIs
Publication statusE-pub ahead of print - 1 Nov 2019

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Histamine H3 Receptors
Histamine Agonists
Amines
Central Nervous System
Cytochrome P-450 Enzyme System
Histamine H3 Antagonists
Response Elements
Structure-Activity Relationship
Luciferases
Reporter Genes
Cyclic AMP
Histamine
Pharmacology
Research

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@article{f56090ec0d0641e2bc72bb43cd430fd1,
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",
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.",
author = "G{\'a}bor W{\'a}gner and Mocking, {Tamara A.M.} and Marta Arimont and Gustavo Provensi and Barbara Rani and Bruna Silva-Marques and Gniewomir Latacz and {Da Costa Pereira}, Daniel and Christina Karatzidou and Vischer, {Henry F.} and Maikel Wijtmans and Katarzyna Kieć-Kononowicz and {De Esch}, {Iwan J.P.} and Rob Leurs",
year = "2019",
month = "11",
day = "1",
doi = "10.1021/acs.jmedchem.9b01462",
language = "English",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",

}

4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity. / Wágner, Gábor; Mocking, Tamara A.M.; Arimont, Marta; Provensi, Gustavo; Rani, Barbara; Silva-Marques, Bruna; Latacz, Gniewomir; Da Costa Pereira, Daniel; Karatzidou, Christina; Vischer, Henry F.; Wijtmans, Maikel; Kieć-Kononowicz, Katarzyna; De Esch, Iwan J.P.; Leurs, Rob.

In: Journal of Medicinal Chemistry, 01.11.2019.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - 4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity

AU - Wágner, Gábor

AU - Mocking, Tamara A.M.

AU - Arimont, Marta

AU - Provensi, Gustavo

AU - Rani, Barbara

AU - Silva-Marques, Bruna

AU - Latacz, Gniewomir

AU - Da Costa Pereira, Daniel

AU - Karatzidou, Christina

AU - Vischer, Henry F.

AU - Wijtmans, Maikel

AU - Kieć-Kononowicz, Katarzyna

AU - De Esch, Iwan J.P.

AU - Leurs, Rob

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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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