posted on 2019-11-20, 14:35authored byGábor 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
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.