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

[Image: see text] 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 (pK(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.