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  • To synthesize the azaindole based

    2021-12-02

    To synthesize the 7-azaindole based compound , Suzuki coupling of 6-chloro-7-azaindole with 4-CFO-phenylboronic TCS HDAC6 20b receptor was carried out in the presence of Pd(dppf)Cl·CHCl to supply biaryl in quantitative yield (). Iodination at the C-3 position resulted 3-iodo-7-azaindazole . Alkylation of the -1 position of with bromide , prepared similarly to as shown in , provide iodide in 82% yield. Suzuki coupling of with 5-trifluoromethyl-2-methoxyphenylboronic acid afforded -butyl ester in high yield, which was hydrolyzed to provide desired acid after chiral resolution. Similarly, synthesis of indole-based compound is shown in . Briefly, 6-bromoindole was alkylated at the -1 position with bromide , and the resulting indole was iodinated at the C-3 position to afford . Suzuki coupling of with 5-trifluoromethyl-2-methoxyphenylboronic acid afforded methyl eater , which was hydrolyzed to acid , and coupled with β-alanine ethyl ester to provide . The second Suzuki coupling of with substituted phenylboronic acids followed by ester saponification afforded desired compounds . The compounds thus synthesized were first evaluated in vitro using both binding and functional assay formats. The binding affinity of compounds for the human glucagon receptor (hGCGR) was determined by their ability to displace [I] Glucagon from hGCGR using a membrane preparation from a CHO cell line expressing the human GCGR (CHO hGCGR). The functional activity was assessed by the ability of these compounds to inhibit glucagon-induced cAMP production in a cell line expressing hGCGR. Both binding and functional activities are expressed as values of IC. All data reported are from the more active enantiomers tested unless otherwise noted. Based on the structure homology of MK-0893 and indazole GRAs designed, it is obvious that the C-3 aryl (Ar) of is critical for the activity against the hGCGR. However, it is not as clear as to where the second aryl substituent (Ar) should be placed on the indazole ring. We therefore set out to compare all C-5, C-6, and C-7 positions of TCS HDAC6 20b receptor indazole. As shown in , we were pleased to find that all indazole-based GRAs were active in vitro against the hGCGR. However, it is clear from the SAR that C-7 is the least preferred position for the second aryl substitution ( and ). While both C-5 and C-6 afforded GRAs with potent activity, C-6 position seems to be more preferred with an edge over C-5 position ( vs , and vs ). With the identification of the C-6 position being the preferred position for the 2nd aryl substitution, we set out to find out how the indazole core compared to other 6/5 ring systems such as indole or azaindole (). Interestingly, while head to head comparison of C-3/C-6 substituted indazoles with corresponding indoles showed very similar activity in binding to the hGCGR, indoles exhibited ca. 5-fold weaker potency in the cAMP functional assay ( vs , and vs ). Indazole was found to be a very potent GRA in both binding assay (IC=1nM) and cAMP functional assay (IC=5.6nM). However, moving the nitrogen at indazole 2 position to 7 position, in another word, replacement of indazole core of with a 7-azaindole core, resulted in significant loss of hGCGR activity (binding IC=12nM, cAMP IC=360nM for 7-azaindole indole ). Obviously, the indazole core is the most preferred scaffold for hGCGR activity among the three heterocycles studied. Aryl substitution on the C-3 position of indazole was then examined for their hGCGR activity (). In general, most of the aryl groups, including substituted phenyl, pyridinyl, or pyrimidinyl groups, are tolerated. Evidently, phenyl groups substituted with simple halides, a methoxyl group, or a trifluoromethyl group is more likely to provide GRAs with good potency (–, and –). A polar substitution on the phenyl group is usually less preferred (, , and ), and often resulted in weaker functional activity ( and ). Similarly, placement of substituted pyridines (–) and pyrimidine () generally afforded compounds with weaker hGCGR activity. Not surprisingly, , an analog of with a 1-MeO-4-CFO-phen-2-yl group at C-3 position, exhibited best functional activity (cAMP IC=11nM) among all aryl groups tested, and excellent binding activity (IC=7.0nM).