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 Gα_i2 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.

Keywords:

• histamine
• H₃ receptors
• H₄ receptors
• drug-likeness

Acknowledgments

Support to BS was provided by a UAEU Program for Advanced Research (UPAR) 2013 Grant (# 31M126), UAE University, and we greatly thank Professor JC Schwartz (Bioprojet, Saint-Grégoire, France) for providing HEK-293 cells stably expressing recombinant hH₃R. We also gratefully thank Professor R Seifert (Hannover, Germany) for providing Sf9 cells and baculovirus stock solutions encoding for hH₄R and G-protein G_αi2 and G_β1γ2 subunits. Support for this work was also provided to HS by the EU COST Actions BM0806, BM1007, CM1103, and CM1207, DFG INST 208/664-1 FUGG as well as the Hesse LOEWE Schwerpunkte Fh-TMP, OSF and NEFF, Merz Pharmaceuticals, and the Else KrönerStiftung, TRIP.

Disclosure

The authors declare no conflicts of interest in this work.