A pharmacophore for high affinity PAF antagonists II. Hydrophobicity study using the molecular lipophilicity potential

Platelet-activating factor (PAF) is a powerful phospholipid-derived autacoid involved in many physiopathological mechanisms. Many PAF antagonists have been synthesized and evaluated as therapeutic candidates. In a previous report, we have described an electronic pharmacophore of PAF antagonists using the molecular electrostatic potential. In the present study, a molecular lipophilicity potential is used to compare the hydrophobic properties of 49 'heterocyclic sp² nitrogen' highly potent PAF antagonists, belonging to six structurally different series (nine hetrazepines, five pyrrolo[1,2-c]thiazoles, 14 carboxamides, nine dihydropyridines, nine pyridinel-thiazolidines and three imidazo[4,5-c]pyridines). Their common features consist of three hydrophilic (HYDz, HY14₃B and HYD3) and two lipophilic zones (LIP₃ and LIP₄), defining the lipophilic pharmacophore of the antagonists. This pharmacophore is also characterized by several zone-to-zone distances: HYD₃-HYD₂ = 1.3 ± 1.0 Å, HY₃B-HYD₂ = 7.8 ± 1.1, HYD₃-HY₃B = 5.1 ± 1.1 Å, LIP₄-LIP₃ = 5.4 ± 1.1 Å, LIP₃-HYD₂ - 11.3 ± 1.6 Å, LIP₃-HY₃B = 5.9 ± 1.0 Å, LIP₃-HYD₃ = 4.3 + 0.9 Å, LIP₄-HYD₂ = 14.7 ± 1.6 Å, LIP₄-HY₃B = 8.1 ± 1.2 Å and LIP₄-HYD₃ = 3.9 ± 1.1 Å. These results represent a new step in the determination of a global pharmacophore for PAF antagonists.