title: Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands.
abstract: A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2-7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N (4)-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N (4)-benzyl-N (2)-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (k(i) =4.49 ± 1.25 nM) and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5-650 nM), moderate to low hH4R affinity (4,500-30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8-6,500), and promising calculated drug-likeness properties.
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Schreeb
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Frankfurt, Germany ; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: Johannes Stephan
authors.initials: JS
authors.lastname: Schwed
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Weizel
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D004305:Dose-Response Relationship, Drug; D018494:Histamine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018494:Histamine Agents; D008024:Ligands; D011743:Pyrimidines; D018100:Receptors, Histamine H3; C012180:2-aminopyrimidine
keywords: H3 receptors; H4 receptors; drug-likeness; histamine