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  • The MeO CFO phen yl group was then selected

    2022-06-29

    The 1-MeO-4-CFO-phen-2-yl group was then selected for the C-3 position when we investigated the aryl substituents at the C-6 position of indazole. As shown in , C-6 position seems to be more tolerant than the C-3 position, as all the aryl groups examined exhibited potent hGCGR activity. Interestingly, even methoxypyridinyl group (, binding IC=3.4nM), which is not well tolerated in C-3 position (, binding IC=26nM), is well accepted. 4-Methoxyphenyl (, binding IC=1.9nM), 4-methylphenyl (, binding IC=2.6nM), and 4-trifluoromethylphenyl (, binding IC=0.8nM) groups, are among the most preferred aryl groups identified at the C-6 position. Our attention was then focused on the -1 benzylic position of indazole. As shows, a small alkyl group at this position is clearly preferred, as no substitution resulted in much weaker hGCGR activity (, binding IC=39nM, cAMP IC=140nM). This is consistent with the findings on the pyrazole-based GRAs exemplified by MK-0893. Although there is no clear difference among small alkyl groups investigated for the hGCGR binding activity (binding IC=2-4nM), their cAMP functional activity suggested that a -butyl, -propyl, and methyl group (, , and , cAMP IC=6.6, 5.0, and 8.0nM, respectively), is more preferred than an isopropyl or ethyl group ( and , cAMP IC=69 and 21nM, respectively). As the pyrazole-based GRAs were often found not to be highly selective against human glucose dependent insulinotropic peptide receptor (hGIPR), one of other class B GPCR’s, selected compounds were screened in hGIPR cAMP assay to verify selectivity of this series of GRAs. A compound’s hGIPR cAMP potency was determined in CHO HC 067047 receptor expressing human GIPR, measuring cAMP production. As shown in , these indazole based GRAs were found to be generally very selective against hGIPR, with selectivity ranging from 79- to 250-fold. Based on their favorable in vitro profiles, several compounds were chosen for in vivo pharmacokinetic characterization in rat. The pharmacokinetic parameters are summarized in . All compounds studied exhibited relatively low clearance, and moderate to long half-lives (1.5–9.7h). Oral dosing of these compounds in rat also found them to possess good exposure and low/moderate to good bioavailability (9–44%), consistent with their low clearance. Encouraged by these desired in vitro profile and pharmacokinetic properties, we studied compound in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice. As shown in , compound was found to be active in blunting glucagon-induced glucose excursion when dosed orally at 1, 3, and 10mg/kg (mpk) one hour prior to a glucagon challenge (IP, 15 μg/kg). The drug levels at 60 min were found to be 0.18, 0.50, and 2.54 μM for 1, 3, and 10mpk dose groups, respectively. Compound was further evaluated for its efficacy in glucose lowering in a hGCGR ob/ob mice in an acute model as shown in . Compared to vehicle control group, compound at 3mpk oral doses lowered blood glucose level significantly at all the time points checked during the 6h post treatment monitoring, highlighting the excellent efficacy of compound in this ob/ob mice model. The drug levels at 1, 3, and 6h were found to be 0.40, 0.28, and 0.12 μM, respectively. In summary, a novel series of indazole- and indole-based compounds was designed based on an earlier pyrazole-based GRA lead MK-0893 and synthesized. Structure–activity relationship studies of this series of compounds focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the -1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in hGCGR mice at doses as low as 1mpk, and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3mpk dose. Further evaluations of these exciting new GRAs are underway and will be reported in due course.