Synthesis and Structure−Activity Relationships of Cyanoguanidine-Type and Structurally Related Histamine H4 Receptor Agonists

• Published in: Journal of medicinal chemistry Vol. 52; no. 20; pp. 6297 - 6313
• Main Authors: Igel, Patrick, Geyer, Roland, Strasser, Andrea, Dove, Stefan, Seifert, Roland, Buschauer, Armin
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 22-10-2009
• Subjects: Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Drug Discovery; Guanidine - analogs & derivatives; Guanidine - chemistry; Guanidine - pharmacology; Guanidines - chemistry; Guanidines - pharmacology; Guanosine Triphosphate - metabolism; Histamine Agonists - chemistry; Histamine Agonists - pharmacology; Humans; Hydrolysis - drug effects; Immunomodulators; Isotope Labeling; Medical sciences; Mice; Models, Molecular; Pharmacology. Drug treatments; Protein Conformation; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Receptors, Histamine - chemistry; Receptors, Histamine - metabolism; Receptors, Histamine H4; Structure-Activity Relationship; Substrate Specificity; H4 histamine receptor; Imidazole derivatives; Agonist; Structure activity relation; Guanidines; Chemical synthesis; In vitro; Organic sulfide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900526h

Recently, we identified high-affinity human histamine H3 (hH3R) and H4 receptor (hH4R) ligands among a series of NG-acylated imidazolylpropylguanidines, which were originally designed as histamine H2 receptor (H2R) agonists. Aiming at selectivity for hH4R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH4R agonist (pEC50 = 7.47, α = 0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pK B = 6.00, α = −0.28), as determined in steady-state GTPase assays using membrane preparations of hH x R-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH4R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH3R inverse agonist (pK B = 8.42, >300-fold selectivity over the other HR subtypes).