The sulfonamide was important for the DP activity no potent

The sulfonamide was important for the DP activity: no potent dual antagonists were identified through the modification of this functional group. Multiple modifications of the phenylacetic Carboplatin moiety have been reported, such as bioisoteric replacements of the carboxylic acid, and the substitutions on the phenyl ring and at the α-position of the phenylacetic acid., shows another modification in the area of the phenylacetic acid, the heterocyclic replacements of the phenyl ring. Most of the heterocyclic replacements resulted in a reduction in potency, especially for DP. The benzofuran derivative () was an exception. It maintained the CRTH2 potency and slightly increased the DP potency in buffer. However, the improved DP binding potency in buffer was not maintained in the presence of plasma, as compared to that of AMG 009 (data not shown). The results of bisaryl ether linker study are shown in . It was found that the methylene linker () moderately improved the binding to the DP receptor. The increased binding potency was also diminished in the presence of plasma, possibly due to higher plasma protein binding. Other linkers, such as the sulfide (), sulfoxide () and sulfone (), all decreased the potencies, especially the DP potency. In general, optimization in the areas of phenylacetic acid, sulfonamide and ether linker was not fruitful in identifying balanced dual antagonists. Optimization in the area of the amide proved to be key for improving DP activity (). Replacing the amide functional group with a heterocycle proved to be a successful strategy. The heterocycles with NH were good replacements for the -butyl amide, such as those in compound , and –. Compound is a more balanced dual antagonist; its DP potency was significantly improved compared to that of AMG 009 (). The oxadiazole (), which has no NH, had significantly weaker CRTH2 potency. Compounds and were also evaluated for their CRTH2 and DP functional activities, and compound was also more potent in inhibiting DP functional activity than AMG 009. Compounds and inhibited human eosinophil shape change mediated by PGD through the CRTH2 receptors with Kb of 0.18nM and 0.084nM, respectively. AMG 009 had a Kb of 0.050nM in the same test. They also inhibited PGD induced cAMP response mediated by DP in platelets in 80% human whole blood with Kb of 50nM and 5nM, respectively, while AMG 009 had a Kb of 42nM. Since CRTH2 and DP share little sequence homology, it is not surprising to see a divergent SAR for the two receptors in this chemical series. This phenylacetic acid series is versatile. It satisfies the demand of the two receptors unrelated in GPCR family and in sequence. We recently reported that selective antagonists for CRTH2 and DP were generated through modifications in the areas of sulfonamide and phenylacetic acid. We also reported that more balanced dual antagonists, such as AMG 853, were discovered through combining good modifications in the areas of amide, phenylacetic acid and phenyl substituents of the phenyl sulfonamide. Here we demonstrate that heterocyclic replacement of the amide of AMG 009 can also yield more balanced dual antagonist, such as . Its DP potency was significantly improved and its CRTH2 potency was maintained compared to AMG 009.