2,4-Diaminopyrimidines as dual ligands at the histamine H1 and H4 receptor - H1/H4-receptor selectivity

Distinct diaminopyrimidines, for example, 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine are histamine H-4 receptor (H4R) antagonists and show high affinity to the H4R, but only a moderate affinity to the histamine H-1 receptor (H1R). Within previous studies it was shown that an aromatic side chain with a distinct distance to the basic amine and aromatic core is necessary for affinity to the human H1R (hH(1)R). Thus, a rigid aminopyrimidine with a tricyclic core was used as a lead structure. There, (1) the flexible aromatic side chain was introduced, (2) the substitution pattern of the pyrimidine core was exchanged and (3) rigidity was decreased by opening the tricyclic core. Within the present study, two compounds with similar affinity in the one digit mu M range to the human H1R and H4R were identified. While the affinity at the hH(1)R increased about 4- to 8-fold compared to the parent diaminopyrimidine, the affinity to the hH(4)R decreased about 5- to 8-fold. In addition to the parent diaminopyrimidine, two selected compounds were docked into the H1R and H4R and molecular dynamic studies were performed to predict the binding mode and explain the experimental results on a molecular level. The two new compounds may be good lead structures for the development of dual H-1/H-4 receptor ligands with affinities in the same range. (C) 2015 Elsevier Ltd. All rights reserved