Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl-guanidines at the four histamine receptor subtypes: a bioisosteric approach

In the search for potential bioisosteres of the 4-imidazolyl ring in acylguanidines (e.g. UR-AK24), known to possess affinity to several histamine receptor subtypes (H_xR, x = 1–4), and cyanoguanidine-type H₄R agonists (e.g. UR-PI376), the contribution of various heterocycles to agonism, antagonism and HR subtype selectivity was studied (recombinant human H_1,2,3,4Rs, isolated guinea pig organs (H₁R, H₂R)). While minor structural modifications of UR-PI376 analogues were not tolerated regarding H₄R agonism, in the case of the acylguanidines, a 1,2,4-triazole ring shifted the selectivity toward the H₂R.