A PROPOSED COMMON SPATIAL PHARMACOPHORE AND THE CORRESPONDING ACTIVE CONFORMATIONS OF SOME TXA2 RECEPTOR ANTAGONISTS

Four pharmacophore recognition sites have been proposed for active thr omboxane A2 (TxA2) antagonists. We have sought to define the correspon ding spatial pharmacophore for these four sites by performing conforma tional analysis and molecular superposition studies on rive known anta gonists: SQ 29,548, SQ 28,668, SQ 27,427, BM 13.505, and a Merck Fross t compound. The strategy was to identify a low-intramolecular-energy c onformer state for each antagonist for which the relative locations an d orientations of the corresponding recognition site groups were in co mmon when all rive antagonists were superimposed. The conformations us ed in the successful molecular superpositions were, then postulated to be the active conformations of each antagonist. Since SQ 29,548 is th e most potent of the five antagonists, it was considered the reference structure in the molecular superposition. A unique spatial pharmacoph ore was identified and may be a useful template in designing a new TxA 2 antagonists.