Design, synthesis and antihistaminic (H-1) activity of some condensed 2-(substituted) arylaminoethylpyrimidin-4(3H)-ones

The synthesis and potential H-1 receptor antagonistic activity of two novel series of condensed 2-arylaminoethylpyrimidin-4(3H)-ones (4, 5) and 4-amin o-2-arylaminoethyl pyrimidines (6) have been reported. Ah the novel compoun ds were found to antagonize histamine in a competitive and reversible manne r. When tested on guinea-pig ileum, compounds exhibited H-1-antagonistic ac tivity, (pA(2) values) in the range of 8.6 to 9.7. Some of the lead compoun ds were evaluated by an in vivo method and were found to protect the guinea pigs against the histamine induced asphyxic shock at the doses comparable to or lower than those of the standard drugs, cetirizine (CAS 83881-51-0) a nd terfenadine (CAS 50679-08-8). The pA(2) acetylcholine values of some of the lead compounds reflect about 1000-fold selectivity for histamine (H,) r eceptors. The 4-aminopyrimidines (6) were found to be more selective than their 4-one analogs (4, 5). In the radioligand binding study, one of the lead compound s, 6e, was found to bind reversibly at the histamine H-1 receptor with the K-i value of 1.3 mu mol/l and IC50 of 3.8 mu mol/l. The lead compounds were found to have negligible sedative potential when tested in vivo. An indirect type of molecular modeling approach, using temelastine (CAS 861 81-42-2) as the standard ligand, indicates that the potent activity of 4, 5 and 6 may be due to the increased spacer chain length between the pyrimidi ne nucleus and the sidechain aromatic ring.