Synthesis, antiplatelet activity and comparative molecular field analysis of substituted 2-amino4H-pyrido[1,2-a]pyrimidin-4-ones, their congeners andisosteric analogues

2-(1-Piperazinyl)-4H-pyrido[1,2-a]pyrimidin-4-one (5a) is a recently descri bed in vitro inhibitor of human platelet aggregation which specifically inh ibits the activity of high affinity cAMP phosphodiesterase. A number of sub stitution derivatives, isosteres, and analogues of 5a were now synthesized and tested in vitro for their inhibitory activity on human platelet aggrega tion induced in platelet-rich plasma by ADP, collagen, or the Ca2+ ionophor e A23187. Among the most effective compounds, the 6-methyl, 8-methyl and 6, 8-dimethyl derivatives of 5a resulted nearly as active as the lead when pla telet aggregation was induced by ADP or A23187, but less active when collag en was the inducer. On the basis of present results and those previously ob tained by us in this and 2-aminochromone structural fields, we have develop ed a statistically significant 3-D QSAR model, using comparative molecular field analysis (CoMFA), describing the variation of the antiplatelet activi ty in terms of molecular steric and electrostatic potential changes. (C) 20 00 Elsevier Science Ltd. All rights reserved.