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Despite the high diversity of histamine H 3 receptor (H 3 R) antagonist/inverse agonist structures, partial or full H 3 R 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 H 3 R 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 H 3 R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 ( 14d ) combines nanomolar on-target activity (p K  i = 8.5, pEC 50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H 3 R 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 H 3 R research.

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