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  • It has been reported about

    2021-03-01

    It has been reported about the synthesis of benzyl bromide in our previous reports, as shown in , , The synthetic route of compounds – is depicted in , Briefly, the synthesis of pyrimidinedione derivatives was started from commercially available recently . After alkylation of material with 1-bromo-2-butyne or 2-cyanobenzo-5-fluorobenzyl bromide, the resulting precursor was transformed into through the -alkylation. Compound was obtained by a process of replacing the 6-chloro group with ()-3-(Boc-Amino) piperidine. Finally, removal of Boc with TFA produced the final compounds –. The inhibitory effects of compounds on DPP-4 activity were evaluated based on fluorescent probe. In this part, we found that three compounds , , showed potent inhibitory activity of DPP-4 at 100 nM with inhibitory rate of (100.12 ± 0.54)%, (95.59 ± 3.7)%, (98.84 ± 0.66)%, respectively (). As shown in , compounds , and exhibited potent DPP-4 inhibitory activity, with IC values of 64.47 nM, 188.7 nM and 65.36 nM. From the data of , we found that the degree of bromination of these compounds may have a close relationship with their DPP-4 inhibitory activity. For example, the number of bromine of compounds – gradually increases from 0 to 3. However, the DPP-4 inhibition rates of compounds – decrease from 100.12% to 0.66%. Similarly, compounds – were less potent than compound . It could be found that their inhibitory rates decreased with the increase of the degree of bromination on phenol moiety. Furthermore, the degree of bromination of these compounds may have a close relationship with their lipid/water partition coefficient (Log P). For example, the DPP-4 inhibition rates of compounds – decrease from 86.8% to -0.87% with the increase of Log P. In addition, the compounds (, ) with fluorocyanobenzyl substituent were more active than the compounds (, ) with butynyl group (). SAR studies showed that fluorocyanobenzyl was crucial since it formed a hydrogen bond with Arg125. Moreover, π-π interaction also explained its enhanced binding affinity (). To further study the hypoglycemic effect of compound , blood glucose levels were measured during 4 weeks treatment. In order to improve the solubility, the succinate salt of compound was prepared according to the method of Hu et al. The dynamic effects of compound on water intake and body weight were recorded during four weeks treatment in BKS mice. There was no difference in water intake and body weight at the baseline (A and B). As shown in A, there was a decrease trend in mean water intake from the second week in compound - or metformin-treated group. However, both compound and metformin had no effect on body weight of BKS mice (B). A lot of abdominal fat was developed in BKS mice at the fourth week (C). Compound or metformin was unable to block the increased ratio of abdominal fat (D). In comparison with BKS mice, diabetic BKS mice exhibited hyperglycaemia with blood levels of about 30 mM (). A trend towards decrease in blood glucose levels was revealed in compared with vehicle and compound /metformin-treated groups. The blood glucose levels were reduced from the second week in both compound and metformin treated group (). These results reveal that compound has anti-diabetic potency with an effective blood glucose-lowing effect. In summary, a series of pyrimidinedione derivatives were designed and evaluated for DPP-4 inhibitory activity and anti-hyperglycemic efficacy. The preliminary SARs analysis exhibits that: (a) hydrophobic property was important for the inhibitory activity of DPP-4. Lipid/water partition coefficient may affect their inhibitory activity of DPP-4; (b) the inhibitory rates increase with the decrease of the number of bromine atoms on phenol moiety; (c) the alkyl side chain could affect the DPP-4 inhibitory activity. (d) fluorocyanobenzyl was crucial for the inhibitory activity of DPP-4. Among them, the representative compounds , and showed strong inhibitory activity of DPP-4 with IC values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound are potent hypoglycemic effect. Potentially, compound is a promising DPP-4 inhibitor and worth further development.