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  • Compounds were tested for GPR activity in a functional assay

    2021-11-26

    Compounds , were tested for GPR40 activity in a functional assay monitoring calcium flux in CHO TC-I 2000 transiently transfected with human GPR40 gene. As shown in , compound was found to be a nanomolar GPR40 agonist, while compound was much less potent than . To explore the structure activity relationship of this new scaffold, a series of compounds with different substitution patterns on the left and middle phenyl ring were synthesized and tested as GPR40 agonists. The results were summarized in . 2,6-Dimethyl substitution on left phenyl ring was found to be optimal for GPR40 agonistic activity (, ), while introduction of fluorine at R position improved activity ( vs , vs ,). Introduction of fluorine substitutions at R, R, and R positions gave mixed results, while in all cases, the diastereomers were more potent than its counterparts. Compound and were selected for further profiling in vivo (). Oral administration of (50mg/kg) and TAK-875 (20mg/kg) in high fat feasted ICR mice 15min prior to dextrose challenge in an oral glucose tolerance test (OGTT) significantly reduced blood glucose excursion. Compounds failed to exhibit any efficacy in this test, probably due to high clearance of the compound in mice (data not shown). Although exhibited some oral efficacy in mice OGTT test, it appeared to be less potent than TAK-875. We then went further to modify these compounds to improve their in vitro and in vivo GPR40 activity. Elimination of the 3-(methylsulfonyl)propan-1-ol tails in compounds – gave another series of GPR40 agonists. These compounds were synthesized similarly as and tested as GPR40 agonists (). To our surprise, compounds without the 3-(methylsulfonyl)propan-1-ol tails generally exhibited improved GPR40 agonistic activity. Also noteworthy in this series of compounds is the activity difference between the and diastereomers were generally smaller, opposite to the SAR in compounds with the sulfone tails in . We hypothesized that the lack of the sulfone tail could render the molecule with more flexibility to fit the binding pocket, therefore minimized the potency differences between the two diastereomers. Compounds with one or two methyl substitution at 2,6 position of the left phenyl ring were found to be most potent in GPR40 assay (, , ). Chlorine, Fluorine or trifluoromethyl substitution at 2,6 positions resulted in less potent compounds (, , , , ). Compounds without 2,6 substitutions at the left ring were less potent in GPR40 assay (, ). Compound was tested in high fat feasted ICR mice OGTT test and was found only moderately active in this in vivo model (9.7% inhibition of AUC, <0.005). During profiling of the above compounds, a compound without a left phenyl ring (, ) was noticed, exhibiting good GRP40 agonistic activity, indicating the left phenyl ring may not be necessary for GPR40 activity. This observation was further explored by introducing different substitutions onto the middle phenyl ring and the results were summarized in . Compounds with a meta bromo-, chloro-, or trifluoromethyl substitution or meta, para di-chloro substitution at the middle phenyl ring were found to be highly potent in GPR40 assay (, , , ), however, para bromo-substitution was not tolerated (). diastereomers were generally more potent than diastereomers. 3,5-Disubstitution resulted in diminished GPR40 agonistic activity (, ). Compounds , , and were selected for pharmacokinetic profiling in rats, dogs and monkeys (). These compounds are characterized by low clearance and volume of distribution, consistent with high plasma protein binding, as well as long half-life and good oral bioavailability. Compounds , , and were then pushed forward to in vivo profiling. To our surprise, none of them exhibited significant in vivo efficacy in our ICR mice OGTT test after a 50mg/kg single dosage (: 4.9% inhibition of AUC, <0.005; : 10.98% inhibition of AUC, <0.005; : 4.9% inhibition of AUC, <0.005; : 13.3% inhibition of AUC, <0.005). This discrepancy between in vitro and in vivo results promoted us to conjecture that their GPR40 activity maybe different among species tested.