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

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 pyridinyl-thiazolidines and three imidazo[4,5-c]pyridines). Their common features consist of three hydrophilic (HYD2, HY14(3)B 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 A, HY3B-HYD2 = 7.8 +/- 1.1, HYD3-HY3B = 5.1 +/- 1.1 A, LIP4-LIP3 = 5.4 +/- 1.1 A, LIP3-HYD2 = 11.3 +/- 1.6 A, LIP3-HY3B = 5.9 +/- 1.0 A, LIP3-HYD3 = 4.3 +/- 0.9 A, LIP4-HYD2 = 14.7 +/- 1.6 A, LIP4-HY3B = 8.1 +/- 1.2 A and LIP4-HYD3 = 3.9 +/- 1.1 A. These results represent a new step in the determination of a global pharmacophore for PAF antagonists.