Drug-likeness approach of 2-aminopyrimidines as histamine H(3) receptor ligands

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 H(3) receptors (hH(3)Rs) stably expressed in HEK-293 cells and human H(4)Rs (hH(4)Rs) co-expressed with Gα(i2) and Gβ(1)γ(2) 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 hH(3)Rs, 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 hH(3)R pharmacophore resulted in N(4)-benzyl-N(2)-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH(3)R affinity (k(i) =4.49±1.25 nM) and H(3)R 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 H(3)R ligands, results showed that integration of the hH(3)R pharmacophore in hH(4)R-affine structural scaffolds resulted in compounds with high hH(3)R affinity (4.5–650 nM), moderate to low hH(4)R affinity (4,500–30,000 nM), receptor subtype selectivity (ratio hH(4)R/hH(3)R; 8–6,500), and promising calculated drug-likeness properties.