Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl-guanidines at the four histamine receptor subtypes: a bioisosteric approachElectronic supplementary information (ESI) available: Synthesis procedures, analytical data and pharmacological methods. See DOI: 10.1039/c3md00245d

• Main Authors: Geyer, Roland, Igel, Patrick, Kaske, Melanie, Elz, Sigurd, Buschauer, Armin
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c3md00245d

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 x R, x = 1-4), and cyanoguanidine-type H 4 R agonists ( e.g. UR-PI376), the contribution of various heterocycles to agonism, antagonism and HR subtype selectivity was studied (recombinant human H 1,2,3,4 Rs, isolated guinea pig organs (H 1 R, H 2 R)). While minor structural modifications of UR-PI376 analogues were not tolerated regarding H 4 R agonism, in the case of the acylguanidines, a 1,2,4-triazole ring shifted the selectivity toward the H 2 R. In the search for potential bioisosteres, the 4-imidazolyl ring in acylguanidine- and cyanoguanidine-type histamine receptor ligands was replaced by various heterocycles. The compounds were investigated for agonism/antagonism and selectivity on the four histamine receptor subtypes.