Abstract
Bioisosteric replacement of the guanidino group in arpromidine‐like histamine H~2~ receptor (H~2~R) agonists by an acylguanidine moiety is useful for obtaining potent H~2~R agonists with improved oral bioavailability and blood–brain barrier penetration. We show that bioisosteric replacement of the imidazole ring in N^G^‐acylated imidazolylpropylguanidines by a 2‐aminothiazol‐5‐yl group resulted in potent H~2~R agonists with much greater selectivity for the human H~2~R over H~3~ and H~4~ receptors.magnified image
The bioisosteric replacement of the guanidino group in arpromidine‐like histamine H~2~ receptor (H~2~R) agonists by an acylguanidine moiety is a useful approach to obtain potent H~2~R agonists with improved oral bioavailability and blood–brain barrier penetration. Unfortunately, the selectivity of such N^G^‐acylated imidazolylpropylguanidines for the H~2~R is poor, in particular versus histamine H~3~ (H~3~R) and H~4~ receptors (H~4~R). This drawback appears to depend on the “privileged” imidazolylpropylguanidine structure. The 2‐amino‐4‐methylthiazol‐5‐yl moiety is a bioisostere of the imidazole ring in the moderately potent H~2~R‐selective histamine analogue amthamine. This approach was successfully applied to acylguanidine‐type H~2~R agonists. The aminothiazoles are nearly equipotent to the corresponding imidazoles as H~2~R agonists. Compared with histamine, the potency is increased up to 40‐fold on the guinea pig right atrium, and up to 125‐ and 280‐fold in GTPase assays with human and guinea pig H~2~R–G~s__α__S~ fusion proteins expressed in Sf9 insect cells, respectively. Docking studies on H~2~R models support the hypothesis that 2‐aminothiazolyl and imidazolyl derivatives interact with H~2~Rs as bioisosteres. In contrast to the imidazoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H~1~, H~3~, and H~4~ receptors. Moreover, unlike amthamine, the 4‐methyl group does not significantly contribute to the H~2~R agonism of N^G^‐acylated 2‐amino‐4‐methylthiazol‐5‐ylpropylguanidines.