SYNTHESIS AND ANTIALLERGIC ACTIVITY OF PYRIDOTHIENOPYRIMIDINES

The synthesis of a series of pyridothienopyrimidines and their evaluat ion as inhibitors or inducers of the release of histamine from rat mas t cells is reported. The activity was measured after immunological sti mulation with ovoalbumin and chemical stimulation with polymer 48/80 a nd the drugs adryamicin and vinorelbine. The experiments were carried out with and without preincubation of the stimulus with the cells befo re addition of the drug. Several pyridothienopyrimidines show inhibito ry IC50 values in the range 2-25 mu M, indicating they are up to 100 t imes more potent than cromoglycate (DSCG) and 10 times greater than Ke totifen. Compound 91 is a potent inhibitor in all the conditions teste d and shows IC50 = 9-25 mu M. Pyridothienopyrimidines 4l and 9e are ve ry strong inducers of histamine release in the immunological (41, 170- 230%) and chemical (9e, 100-150%) assays, respectively. Compounds 4l a nd 9i are cytotoxic in vitro (IC50 = 0.1-0.2 mu g/mL) against P-388, A -549, HT-29, and MEL-28 tumor cell lines. (C) 1998 Elsevier Science Lt d. All rights reserved.