ICI-185282

A range of thromboxane A2 receptor blocking (TxRB) drugs, prostacyclin and aspirin have been assessed as inhibitors of human platelet deposition onto rabbit and human de-endothelialized arteries in vitro. Platelet deposition was quantified by measuring the radioactivity associated with de-endothelialized arteries following superfusion with 111indium-labelled human platelets reconstituted in blood. Using rabbit aorta, all of the compounds tested produced a similar maximum inhibition (approximately 70%) of platelet deposition; from scanning EM studies the residual deposition appeared to represent a monolayer of adhered platelets. The potency of the TxRB's for inhibiting deposition was GR32191 greater than or equal to GR36246 greater than SQ29,548 greater than ICI185282 greater than or equal to AH23848 much greater than BM13.177 consistent with their TxRB potency on human platelets. Using human umbilical arteries, the TxRB's achieved a smaller maximum inhibition of deposition (approximately 50%) than did prostacyclin or the fibrinogen receptor blocking peptide Gly-Arg-Gly-Asp-Ser (GRGDS) (60-75%). In addition, using human umbilical arteries, the structurally-related TxRB's GR32191 and GR36246 exhibited a greater than 1000-fold enhancement in potency as inhibitors of platelet deposition over that seen in the rabbit aorta. In preliminary experiments, GR32191 also displayed a similar high potency on human cerebral arteries. In contrast, the structurally unrelated compounds SQ29,548, ICI185282 and BM13.177 exhibited similar potencies on human umbilical arteries to those observed on the rabbit aorta; aspirin and prostacyclin also displayed similar potencies on the two preparations. The enhanced effect of GR32191 and GR36246 on human umbilical arteries therefore appears unrelated to their action as TxRB's on human platelets although the mechanism of this unique action is at present unknown. However, if these drugs exhibited a similar high potency for preventing mural thrombus formation in vivo in man, they may represent a major advance in the treatment of occlusive vascular disease.

Derivatized β-cyclodexctrins combined with high field ¹⁹F-NMR were used for determination of enantiomeric purity of ICI 185,282 (I).A major advantage of these materials (apart from the superior ¹⁹F-NMR resolution obtained) is their greater water soluble, compared to β-cyclodextrin.