title: Design, synthesis and antihistaminic (H(1)) activity of some condensed 3-aminopyrimidin-4(3H)-ones.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, L.M. College of Pharmacy, Navrangpura, Ahmedabad, India. bcshishoo@wilnetonline.net
authors.forename: C J
authors.initials: CJ
authors.lastname: Shishoo
authors.forename: V S
authors.initials: VS
authors.lastname: Shirsath
authors.forename: I S
authors.initials: IS
authors.lastname: Rathod
authors.forename: V D
authors.initials: VD
authors.lastname: Yande
mesh_terms: D000818:Animals; D001237:Asphyxia / Q000139:chemically induced / Q000517:prevention & control; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D006168:Guinea Pigs; D006632:Histamine; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D006634:Histamine H1 Antagonists; D006993:Hypnotics and Sedatives; D011744:Pyrimidinones; D006632:Histamine