Acylguanidines as Bioisosteres of Guanidines: N^G-Acylated Imidazolylpropylguanidines, a New Class of Histamine H₂ Receptor Agonists

N¹-Aryl(heteroaryl)alkyl-N²-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H₂-receptor (H₂R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H₂R agonists by 4−5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H₂R. At the hH₁R and hH₃R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH₄R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H₄R agonists.