Drug-likeness approach of 2-aminopyrimidines as histamine [H.sub.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.sub.3] receptors (h[H.sub.3]Rs) stably expressed in HEK-293 cells and human [H.sub.4]Rs (h[H.sub.4]Rs) co-expressed with G[α.sub.i2] and G[β.sub.1][γ.sub.2] subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazm-l-yl)-[N.sup.4]-(3-(piperidin-l-yl)propyl)pyrimidme-2,4-diamme (compound l) with unsatisfactory affinity and selectivity to h[H.sub.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 h[H.sub.3]R pharmacophore resulted in [N.sup.4],-benzyl-[N.sup.2] -(4-(3(piperidin-l-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high h[H.sub.3]R affinity ([k.sub.i] =4.49±l.25 nM) and [H.sub.3]R receptor subtype selectivity of more than 6,500x. 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.sub.3]R ligands, results showed that integration of the h[H.sub.3]R pharmacophore in h[H.sub.4]R-affine structural scaffolds resulted in compounds with high h[H.sub.3]R affinity (4.5-650 nM), moderate to low h[H.sub.4]R affinity (4,500-30,000 nM), receptor subtype selectivity (ratio h[H.sub.4]R/h[H.sub.3]R; 8-6,500), and promising calculated drug-likeness properties. Keywords: histamine, [H.sub.3] receptors, [H.sub.4] receptors, drug-likeness