pyrimidinones and Asphyxia

Anovel series of condensed 3-amino-2-(substituted)methylpyrimidin-4(3H)-ones is reported with potential H(1) receptor antagonistic activity. The IC(50) values for 23 compounds were found to be in the micromolar range. Five lead compounds (10c, e, g, r and t), when evaluated by the in vivo method were found to protect guinea-pigs from the histamine induced asphyxia and antagonized histamine in a competitive and reversible manner. With a pA(2) value of 8.7 and protection time of 9.5 min (in vivo test), compound 10g was the most active amongst these five compounds. The isosteric replacement of the side chain -NH- in series 1, by oxygen and -NHSO(2)- functions, was undertaken to investigate the role of two amino functions in the receptor binding. This isosteric replacement with -O- does not affect the antihistaminic activity and the sedative potential of the series. Preliminary molecular modelling studies indicate that the compounds with -NHSO(2)- in the side chain exhibit a closer fit with temelastine than their -O- isosteres.

Topics: Animals; Asphyxia; Chemical Phenomena; Chemistry, Physical; Drug Design; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hypnotics and Sedatives; Ileum; In Vitro Techniques; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Muscle Contraction; Muscle, Smooth; Pyrimidinones; Spectrophotometry, Infrared; Structure-Activity Relationship