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    • Next we examined the SAR of the amide

    2020-07-28

    Next, we examined the SAR of the amide linker moiety of 15-19 and 15-20 (Table 3). An N-methylamide 15-34, which was devoid of the hydrogen bond donor (NH) showed a 15-fold reduction in the binding affinity (15-34: IC50=210nM), suggesting that the hydrogen bond donor (NH) is likely to contribute to the greater binding affinity. The amide derivatives 15-30–15-32, which differ in the lengths of their linkers, displayed activity comparable to that of the parent Cetrorelix 15-20. It is interesting to note that incorporation of an aminocarbonyloxymethylene linker (15-35) led to a 2-fold improvement in the binding and functional potency. Compounds (15-38 and 15-39) having the inverted amide linkers of 15-19 and 15-20, respectively, had acceptable binding affinity (15-38: IC50=8.2nM, 15-39: IC50=10nM), and functional activity (15-38: IC50=38nM, 15-39: IC50=13nM). In addition, an amidoethylene linker was also tolerable in the CRTH2 binding (15-40: IC50=7.8nM, 15-41: IC50=3.7nM), and the functional potency (15-40: IC50=12nM, 15-41: IC50=18nM). Next, we carried out additional SAR study of the linker moiety. When an aminomethylene (15-36) or urea (15-33) tether was incorporated in place of the amide linker, the resulting compounds maintained the potent CRTH2 binding affinity, but it led to a 2- to 4-fold reduction in functional activity compared to that of 15-19. In contrast, a sulfonamide linker (15-37) led to a significant reduction in the binding (15-37: IC50=340nM). An oxymethylene linker resulted in a slight loss of the binding affinity (15-42: IC50=38nM), and a substantial loss in the functional potency (15-42: IC50=180nM). The oxyethylene and oxypropylene linkers maintained the potent binding affinity (15-43: IC50=12nM, 15-44: IC50=11nM), while the functional activity of these compounds was weak (15-43: IC50=130nM, 15-44: IC50=85nM). We next examined the effects of substituents around the carboxylic acid moiety on CRTH2 binding (Table 4). The carboxylic acid moiety shared by the representative CRTH2 antagonists and is essential for the CRTH2 activity. Germinal dimethylation of the methylene moiety next to the carboxylic acid resulted in a 25-fold decrease in the binding potency (15-45) compared with that of the original compound 15-40, and similarly, the functional activity of 15-45 was dramatically reduced. Insertion of an oxygen atom between the carboxymethyl moiety and the heteroaryl group resulted in a slight loss in the binding and a significant decrease in functional activity (15-46). These data suggest that the binding site of the CRTH2 (P1), where the acid moiety of the antagonists interacts, is strictly limited. The SAR study of the isoquinoline scaffold demonstrated that with a few exceptions, compounds with high binding affinities generally exhibited highly potent functional activities. One of the most potent antagonists, 15-20 (IC50=19nM), was effective in a chemotaxis assay (IC50=23nM) and exhibited sufficient selectivity in binding to CRTH2 over the DP1 prostanoid receptor (IC50 >1μM) and the COX-1 and COX-2 enzymes (IC50 >10μM).