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  • With the nitrogen containing heterocycle components and the

    2021-09-22

    With the nitrogen-containing heterocycle components and the acidic components in hand, the final products were synthesized according to the procedure as depicted in . Reaction of – with various β-substituted phenylpropionic Nifuroxazide (, and ), followed by deprotection by TFA, smoothly provided the corresponding intermediates –, –, respectively. Hydrolysis of – resulted in the formation of products –. Alternatively, compounds – were reacted with alkyl halides or acyl halides, which were then hydrolyzed with sodium hydroxide to yield target products –. The synthesis of compounds – was realized according to the method established above. All compounds were initially evaluated for their GPR40 agonistic activity by detecting luciferase activity in HEK293E cells expressed hGPR40 at a concentration of 10 μM. TAK-875 was employed as the positive compound. The results are summarized in . As can be seen from , the substituents on the nitrogen atom had a remarkable influence on the GPR40 agonistic activity. Compounds – without any substituents on N atom did not show any activity on GPR40 cell. Compounds , and bearing an ethyl group on the N atom only exhibited slight agonistic activities on GPR40. In contrast, introduction of benzyl group led to a dramatic increase of GPR40 agonistic activity . The activities of compounds and were approximately 90% of that of TAK-875, while compounds and exhibited better activities than TAK-875. Compounds (, , and ) possessing a benzoyl group showed moderate activity on GPR40. Increasing the distance between the distal phenyl and N atom as exemplified in compounds , , and resulted in a loss of GPR40 agonistic activity. The position of the six-membered nitrogen-containing heterocycles had little if any effect on the GPR40 agonistic activity, but generally the activity of 1,2,3,4-tetrahydroisoquinoline derivatives was superior to that of isoindoline derivatives. Replacing the acidic component with phenoxyacetic acid and 3-methyl-3-phenyl-butanoic acid led to a reduced GPR40 activity, except compound , which maintained comparable activity with TAK-875. The result was outlined in . As listed in , , several compounds exhibited excellent GPR40 agonistic activity at a concentration of 10 μM, which was similar to or even better than the positive compound TAK-875. To further investigate the activity of these compounds, EC was evaluated and listed in . All tested compounds exhibited comparable activity with TAK-875. The highest activity was observed with compounds , and with the EC value of 1.2 μM, 0.8 μM and 0.8 μM, respectively. The cLogP values of these compounds were also calculated using Molinspiration cheminformatics, which was used to predict their lipophilicity preliminarily (). The result demonstrated that cLogP values of these compounds were generally lower than TAK-875, which suggested this novel series of GPR40 agonists could show a relatively low lipophilicity compared with TAK-875. The direct effect of stimulating insulin secretion of compounds and was evaluated on primary islets isolated from normal ICR mice at a concentration of 10 μM. The result indicated that compounds and could increase insulin secretion in a high concentration of glucose (16.8 mM) ( and ). The cytochrome P450 inhibition of compounds and was then tested at a concentration of 5 μM (). The results showed that compounds and exhibited no significant inhibition against CYP2D6, CYP2C9, CYP3A4 and CYP1A2. Furthermore, we evaluated the efficacy of compounds and by oral glucose tolerance test (oGTT) in normal ICR mice.. Compound effectively reduced the area under the curve of blood glucose (AUC low 13.8%, P < 0.01) after oral glucose administration at 50 mg/kg, however did not have an obvious effect on the blood glucose compared with control group ( and ). To further understand the interaction of this series of GPR40 agonists with GPR40, the molecular simulation between compound and GPR40 protein (the complex structure of GPR40 was obtained from the Protein Data Bank, PDB code: ) was conducted using CDocker protocol with default settings in Discovery Studio 2017 software package (BIOVIA, San Diego: Dassault Systemes). The molecular simulation result indicated compound bound to GPR40 predominantly through a strong hydrogen bond between the carboxyl group with ARG183 and two salt bridges with ARG183 and ARG 2258. Besides, benzene rings were interacted with a number of amino acid residues via Pi-Pi interaction (-CDocker interaction energy = 37.76 kcal/mol, ).