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  • g 36 br Conclusions br Conflicts of


    Conflicts of Interest
    Acknowledgments The Section of Endocrinology and Investigative Medicine is funded by grants from the Medical Research Council (MRC), Biotechnology & Biological Sciences Research Council (BBSRC), National Institute for Health Research (NIHR), an Integrative Mammalian Biology Capacity Building Award, an FP7- HEALTH-2009-241592 European Obesity Consortium studying the Hypothalamus Interaction with Peripheral organs (EuroCHIP) grant, and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the author(s) and not necessarily those of the MRC, BBSRC or the NIHR.
    Type 2 diabetes is characterized not only by insulin resistance and β-cell dysfunction but also by hyperglucagonemia in the fasting state and lack of glucagon suppression following meal ingestion., It is therefore necessary for a complete treatment of type 2 diabetes to include agents that reverse hyperglucagonemia. Glucagon, a peptide hormone consisting of 29 amino g 36 residues and produced in the α-cells of the pancreas, acts in the liver where it binds to the glucagon receptor (GCGR) to initiate gluconeogenesis and glycogenolysis. It has been reported that plasma glucagon levels are abnormally high throughout the day in type 2 diabetic patients. This led to the idea that GCGR antagonists may reduce hepatic glucose output and lower abnormal plasma glucose levels., In fact, Bayer reported that the GCGR antagonist, Bay 27-9955 (, ), suppresses excess glucagon-induced high plasma glucose levels in humans. These findings indicate that GCGR antagonists may be useful in the treatment of type 2 diabetes. To date, a number of non-peptidic GCGR antagonists with various acidic moieties including, β-alanine (NNC 25-0926 and MK-0893, ), tetrazole (), or -cyanophenol () have been reported (). Although some of these compounds proceeded to clinical trials,, none is clinically available. In our search for new chemotypes of GCGR antagonists, we screened our chemical library and found compound , 3,4-diphenylfuran-2-carbohydrazide derivative (), as a hit compound with moderate binding affinity for GCGR (50% inhibition at 10μM in rat hepatocyte). Our strategy for hit to lead generation focused on introducing the acidic moiety (). Initially we replaced the furyl group in with various groups as shown in . Since the phenyl compound exhibited a GCGR binding affinity similar to that of , we next introduced a hydroxy group, as acidic moiety, at the phenyl group of . The obtained -hydroxyphenyl compound showed a slight improvement in GCGR affinity, whereas the -hydroxyphenyl compound gave a loss in GCGR affinity. When the -hydroxy group was masked with a methyl group, the resulting compound showed a complete loss of GCGR affinity. Regarding the other acidic group, benzoic acid showed a slight loss in GCGR affinity compared to the phenol . Introduction of two hydroxy groups () resulted in no improvement in GCGR affinity. Remarkably, further improvement was seen with the hydroxypyridine , which showed a 10-fold IC value improvement compared to the hit compound . Based on these results, it became clear that the p values and GCGR affinity of compounds ,,, had similar variation. These findings suggested that an acidic proton at the -position is needed for high GCGR affinity and that the acidity of the phenol group relates to GCGR affinity. However, a too strong acid such as benzoic acid would not exceptionally be well tolerated. To confirm the relationship between the p values and the affinity for GCGR, we screened substituents at the -position of the phenol shown as R in and calculated the p values of the obtained compounds –. The use of a fluoride () resulted in a remarkable improvement in GCGR affinity with a p value much lower than that of compound . Similarly, a chloride () or a bromide () led to improved GCGR affinity. Compounds possessing a strong electron withdrawing group, such as a trifluoromethyl group () or a nitro group () showed dramatically improved GCGR affinity, especially compound exhibited more than 100-fold improved affinity compared to the hit compound . On the other hand, compounds with electron-donating groups, a methoxy () or a phenyl group () showed no improvement in GCGR affinity compared to . These findings confirmed our hypothesis as good correlation was observed between IC values and p values (correlation coefficient: =0.96, from to in ).