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  • The results of bisaryl ether linker study


    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 4716 australia 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.
    Introduction Prostaglandin D2 (PGD2), derived from arachidonic acid via the cascade reactions of cyclooxygenase, is the major prostanoid released from activated mast cells. The biological actions of PGD2 are mediated by the G-protein-coupled receptors (GPCRs) termed DP1 and CRTH2 (also known as DP2).1, 2, 3 The CRTH2 receptor is expressed on cells including eosinophils, basophils and Th2 cells and is involved in the migration and activation of these cells.4, 5, 6 Particularly, the CRTH2 receptor may have an important role in inflammatory diseases including asthma, COPD, and allergic rhinitis.7, 8 The emerging roles of the CRTH2 receptor in inflammatory diseases led to extensive research aimed at identifying selective CRTH2 antagonists. The research into CRTH2 antagonists dramatically increased after studies identifying ramatroban, a thromboxane receptor antagonist used in the treatment of allergic rhinitis, as a CRTH2 antagonist, as well as reports demonstrating CRTH2 agonism of the anti-inflammatory drug, indomethacin. Starting with related indolacetic acids, such as 1,2 and 3, structure–activity relationship (SAR) information around the indolacetic acids were disclosed. Since then, a large number of CRTH2 antagonists including several series of chemotypes including 5-azaindole (4), 7-azaindole (5), benzimidazole,14, 15 indolizine, spiro–indoline (Fig. 1) have been reported. In the course of our program, aimed at developing CRTH2 antagonists for the treatment of allergic diseases, we pursued a new class of potent and selective CRTH2 antagonist. Figure 2 shows a superposition of four reported CRTH2 antagonists (2, 3, 6 and 7). The alignment model was based on the molecular modeling software MOE. The model shows three overlapping sites with similar chemical features. P1 is a carboxylic acid site, P2 is an aromatic ring, main scaffold including a monocyclic and/or fused-ring system, and P3 consists of an aromatic ring with diverse functional groups. Using a fused 6–6 membered ring system as a core structure, we newly designed a 1,4-disubstituted isoquinoline as a P2 scaffold. As a result, we have identified a novel compound 15-1 showing moderate binding affinity (IC50=330nM) in a radioligand binding assay (3H-PGD2) with the human CRTH2 receptor. A preliminary account of this work has been previously presented, and herein we describe the synthesis and SAR of the new class of isoquinoline derivatives.