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  • As illustrated in Table monocyclic acid analogs were synthes


    As illustrated in Table 3, monocyclic Retaspimycin hydrochloride analogs were synthesized and evaluated. 2-Oxido-3H-1,2,3,5-oxathiadiazol analog 8 showed 15-fold less potent EP1 receptor affinity relative to 2b, while it showed 2.2-fold more potent antagonist activity. Oxadiazole-5-one analog 9 exhibited nearly equipotent receptor affinity and antagonist activity with 8. A thiadiazole-5-one analog 10 showed 2.4-fold less potent EP1 receptor affinity and 1.3-fold less potent antagonist activity relative to 8, while it also showed weak affinity for the EP4 receptor. A tetrazole analog 11 demonstrated the strongest antagonist activity among this series of analogs, although it showed nearly the same receptor affinity as 8–10. Besides, 11 showed an increased affinity for EP3 receptor relative to 8–10. Activity profiles of fused bicyclic acid analogs are shown in Table 4. Analogs 12–14 showed weaker antagonist activity relative to the series of monocyclic acids 8–11, although they showed equipotency in their EP1 receptor affinity and better subtype selectivity. Phthalimide analog 12 showed 31-fold less EP1 receptor affinity and 121-fold less potent antagonist activity relative to 2b. 4-Hydroxyquinazoline analog 13 and 2,4-dihydroxyquinazoline analog 14 exhibited equipotency in their EP1 receptor affinity, while 13 showed 2.9-fold more potent antagonist activity than 14. Second, the effect of transformation of the linker Y (Table 5) between the carboxylic acid residue and the phenyl moiety on receptor affinity and antagonist activity was investigated. Replacement of the carboxylic acid residue of 2b with a propionic acid residue yielded 15, which showed 17-fold less potent EP1 receptor affinity and 30-fold less potent antagonist activity. Replacement of the carboxylic acid residue with a propenoic acid residue and a propynoic acid residue gave 16 and 17, respectively, with 2-fold and 5.5-fold less potent EP1 receptor affinity, while both showed nearly the same antagonistic activity as 2b. Oxyacetic acid analog 18 showed nearly the same EP1 receptor affinity as 16, while it showed 4-fold less antagonist activity, which was weaker than its receptor affinity. Based on the relatively stronger antagonist activity of 2b, 16, and 17, conformational restriction of the acid residue was found to be one of the required partial structures for increased antagonist activity. Optimized compounds 2b, 8–11, and 16 and 17 were also evaluated for their inhibition of P450 enzymes, to predict their potential for drug–drug interactions. As shown in Table 6, monocyclic acid analogs 8–11 exhibited relatively stronger inhibition. Tetrazole analog 11 demonstrated especially strong inhibitory activities against 2C9, 2C19, and 3A4. Propynoic acid analog 17 showed increased inhibitory activities against 2C9 and 3A4 compared with 2b. In summary, we synthesized and evaluated 5-methylfuran-2-sulfonyl analog 2b, which exhibited much stronger antagonist activity than 1 and 2a. Based on the data, the 5-methyl residue of 2b was considered to play an important role in transmitting functional activity via the EP1 receptor. To improve antagonist activity, we also synthesized and evaluated acid analogs of 2b by incorporating the concept of the bioisostere into further optimization. Among the tested compounds, monocyclic acid analogs 8–11 listed in Table 3 exhibited stronger EP1 receptor antagonist activity relative to 2b, although all of them showed weaker receptor affinity. In particular, tetrazole analog 11 showed the strongest antagonist activity among the tested compounds. As a result, the carboxylic acid residue showed the most optimized receptor affinity as illustrated by the analogs 1, 2a and b (Table 1), while the monocyclic acid equivalents showed the most optimized antagonist activity as illustrated by the analogs 8–11 (Table 3). Based on the above-described results, the acidic equivalents of the analogs 4–7 (Table 2) were considered to show decreased antagonist activities because of the more influence of bovine serum albumin (BSA) relative to those of 8–11. Fused bicyclic acid equivalents of the analogs 12–14 were also considered to show much more decreased antagonist activities for their relatively potent binding affinities because of the more influence of BSA such as a presumed increased protein binding.