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  • Next the effects of a phenyl group

    2022-05-19

    Next, the effects of a phenyl group at the 3- and 4-positions of the furan on GCGR affinity were investigated (). Surprisingly, despite the lack of a 4-phenyl group at the furan, compound exhibited almost the same GCGR affinity as compound . On the other hand, when the phenyl group at the 3-position of the furan was removed, GCGR affinity diminished (, and ). Therefore, only the phenyl group at the 4-position of furan was removed from to decrease its molecular weight and lipophilicity. Finally, we optimized the substituents at the -, - or -position of the phenyl ring (shown as R, R, R in ). The -methyl compound exhibited high affinity compared to the -isomer or the isomer . As the -substituent was critical for good affinity, we fixed a mono substituent at the -position of the phenyl ring. The -methoxy compound had weak GCGR affinity compared to the methyl compound . Similarly, the fluoride compound and the chloride compound showed lower affinity than the methyl compound . Since an alkyl group seemed to be preferred to a halogen group, we extended the alkyl chain at the methyl group. As a result, the linear alkyl-chain derivatives ,, showed more potent GCGR binding affinity than . Three potent compounds that is, ,, were selected and evaluated for their inhibition of cAMP production using rat, dog and human primary hepatocytes. As cAMP is known as an intracellular second messenger for downstream signals of GCGR stimulation by glucagon,, GCGR antagonists are believed to inhibit cAMP production in hepatocytes. Among the three selected compounds, compound showed the most potent inhibitory activity of cAMP accumulation (). In addition, compound (1μM) showed no noteworthy binding affinity for over 100 off-targets, including enzymes, receptors, ion 23401 zip code and GLP-1R (), indicating that compound has more than 100-fold selectivity for GCGR. To evaluate the in vivo efficacy of compound , a rat pharmacokinetic study of this compound was performed. As shown in , compound showed good bioavailability with satisfactory long half-life. shows the results of glucagon challenge test of compound in normal rats (=6). Compound was orally administered 30min before intravenous administration of glucagon (3μg/kg). Compound at 30mg/kg significantly inhibited glucagon-induced glucose elevation. Compound suppressed glucose elevation for up to 6h after administration (data not shown). We further investigated the glucose lowering effect of compound using Goto-Kakizaki (GK) rats, which are non-obese type 2 diabetic rats (). Compound (30mg/kg) significantly decreased glucose levels in GK rats. This decreasing effect was sustained for up to 6h after administration. These results indicate that compound acts as a long-term GCGR antagonist not only in normal rats but also in GK diabetic rats. The 3,4-diphenyl furan derivatives were prepared as illustrated in . The acylhydrazide was condensed with various carboxylic acids to afford compounds ,–,, and . Similarly, compound was condensed with various benzoic acids followed by deprotection of the methyl group by BBr, when necessary, to afford compounds ,,–. Compounds – were synthesized as shown in . Suzuki–Miyaura reaction of the ethyl 3-bromofuran-2-carboxylate with various phenylboronic acids gave compound in high yields. The ester group of compound was converted to a hydrazide by hydrazine monohydrate under reflux conditions. Condensation of with 3-nitro-4-acetoxybenzoic acid followed by deprotection of the acetyl group afforded the desired compounds –. Preparation of compound is shown in . Two commercially available fragments and were condensed by BOP reagent to give compound . In summary, we have found furan-2-carbohydrazides as novel scaffold of GCGR antagonists by determining SARs of a series of derivatives obtained by modifying the acidity of the phenol moiety. We have also found that the -nitrophenol is a good scaffold for GCGR antagonistic activity. The most promising compound in our series demonstrated comparatively long-term suppression of glucose level in vivo. Further investigations are currently ongoing.