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    • stavudine synthesis Firstly the impact on activity and selec

    2021-10-09

    Firstly, the impact on activity and selectivity was made by replacing the 2, 3-di-F substitution of ring A with 2,3-OCHO- () and 2-NO () substitutions, and replacing the 3, 5-di-F substitution of ring B with 3,5-di-OMe () and 3,5-di-Me () substitutions. Compound kept moderate activity (EC = 220 nM) and good selectivity over GPR40. The EC value of nitro substitued phenyl was about 1.478 μM. The 3,5-di-Me substitution on the ring B ( resulted in a loss of GPR120 potency (EC = 847 nM), though kept a moderate selectivity. Even 3,5-di-OMe abolished GPR120 activity (). We speculated that this result may be explained by electronic or steric effects. Secondly, we examined the SAR profile of phenoxybutanoic stavudine synthesis side chain (). Replacement of the oxygen atom with sulphur atom led to compound with a moderate activity (EC = 347 nM) and a good selectivity. Compound with a sulfonyl group to replace the oxygen atom completely lost GPR120 agonist activity. Then the acid chain was modified by shortening and lengthening to afford compounds and . The shortening of the chain resulted in loss of activity (). Lengthening the carbon chain to five carbons led to a moderate activity (, EC = 186 nM) and a good selectivity over GPR40, while with a six-carbon chain displayed decreased activity and selectivity. Further extension of the carbon chain (, ) resulted in sharp decrease in both potency and selectivity, favoring GPR40 agonism over GPR120 agonism. Introduction of di-α-methyl group on the phenoxybutanoic acid side chain () was not beneficial for improving the activity and selectivity. Replacement of the acid group by -sulfonylamide group (, ) completely abolished GPR120 agonism activity, indicating that the acid ‘bullet’ was crucial for the GPR120 agonism activity. A probable explanation is that the carboxylic acid group could interact with the key amino acid residue of GPR120 to form a critical hydrogen bond., , Attempt to explore the necessary of the methoxycyclobutoxy group of for GPR120 potency, we replaced the methoxycyclobutoxy group with a simple methoxy group (). To our delight, compound (EC = 69 nM) exhibited better GPR120 potency than but displayed low selectivity. Then we replaced the methoxycyclobutoxy group with 4-methoxytetrahydro-2H-pyran group () and 3-(methoxymethyl)-2-methyl-1,1′-biphenyl group (), we found both of compound and displayed weak activity (). It seems that the methoxycyclobutoxy group is necessary for maintaining the GPR120 agonist activity and selectivity over GPR40. To explore more potent GPR120 agonist with high selectivity over GPR40, further modification of R, R, R and R substituents are still in research in our team. To date, the results showed that the 2, 3-di-F substituent on ring A and 3, 5-di-F substituent on ring B are beneficial for the potency. Besides, it appears that oxygen atom was the most suitable atom in the carboxylic acid side chain. Given the significant GPR120 agonist activity and high selectivity of , this compound was selected for further biological evaluation. Oral glucose tolerance test (OGTT) in ICR mice was performed for and to examine their hypoglycemic activity (, ). The compounds were orally administered 60 min prior to a glucose challenge (2.5 g/kg). Both compounds and exhibited significant reduction of blood glucose at the dose of 10 mg/kg (). Furthermore, displayed a dose-dependent glucose reduction during OGTT. In summary, we have designed and synthesized a series of biphenyl derivatives based on the hybrid design and examined their structure-activity relationship. Some of the compounds showed more potent GPR120 agonist activity and high selectivity over GPR40. Importantly, exhibited dose-dependent hypoglycemic activity in OGTT assay (See ). This study provides a suitable tool compound for the mechanism study in antidiabetic role of GPR120. Further structural modifications are ongoing to search for potential drug candidates for treating diabetes.