br G protein coupled receptor
G-protein coupled receptor 40 (GPR40), also known as a free fatty leukotriene receptor antagonists receptor, is dominantly expressed in pancreatic β cells and intestine K, L cells., . Besides, GPR40 is also reported to be expressed in brain, but its function is still unknown. It is well documented that GPR40 agonist is able to decrease blood glucose level via stimulating the insulin secretion and take effect only when patients suffer from a high blood glucose level, which decreases the risk of hypoglycemia significantly., Moreover, it is reported that GPR40 agonist is able to avoid weight gain effectively, which is a common side effect associated with clinic drugs used for treating type 2 diabetes. Given the advantages mentioned above, GPR40 has become an excellent target for the treatment of type 2 diabetes. To date, multiple classes of GPR40 agonists, bearing a β-substituted phenyl propionic acid in common, have been explored., , , , , , , (). Although TAK-875 was terminated in phase III clinic trial, it is still an important lead compound for discovering novel GPR40 agonists. A great number of structural modifications based on TAK-875 have been carried out, and a common strategy was to introduce polar group into the structure of TAK-875 with the aim of decreasing its lipophilicity. A variety of heterocycles, such as thiazole, isoxazole and pyrrole, has been employed to replace the phenyl ring of biphenyl moiety in TAK-875 and achieved promising results., , , , Inspired by these results, we envisioned to design a novel series of GRP40 agonists by introducing six-membered or five-membered nitrogen-containing heterocyclic rings into the structure of TAK-875. Theoretically, the introduction of nitrogen-containing heterocycles could decrease lipophilicity of these newly designed compounds. The N-H group of the heterocyclic rings could be further acylated or alkylated to give structurally diversified derivatives. In the meantime, the acidic component of TAK-875 could be replaced by other β-substituted phenylpropionic acids. The structural modification plan was depicted in . Totally, 34 compounds were synthesized with three different acidic heads and four different nitrogen-containing heterocyclic rings. Compound was discovered as the promising lead compound for further investigation, as it exhibited comparable GPR40 agonistic activity (EC = 1.2 μM) and relatively lower lipophilicity (cLogP = 1.3) compared with TAK-875 (EC = 5.1 μM, cLogP = 3.4). It also showed no obvious inhibition against cytochrome P450 (CYP450). Besides, compound was able to increase insulin secretion of primary islets isolated from normal ICR mice, and in oral glucose tolerance test (oGTT) in normal ICR mice, compound also showed efficacy. The nitrogen-containing heterocycles selected in this work involve 1,2,3,4-tetrahydroisoquinoline and isoindoline. The synthetic route of nitrogen-containing heterocycle components was shown in . The synthesis of compounds – containing a tetrahydroisoquinoline moiety started from bromo substituted phenylacetonitrile. Reduction of bromo substituted phenylacetonitrile – with BH in THF gave compounds –, which were then converted to compounds – in the presence of ethyl chloroformate and triethylamine. Cyclization of compounds – with paraformaldehyde in formic acid afforded the intermediates –. Compounds – were treated with potassium hydroxide, followed by protection of the amino group with (Boc)O to form compounds –. The coupling reaction of compounds – with 3-(hydroxymethyl)phenylboronic acid catalyzed by Pd(PPh) resulted in the formation of tetrahydroisoquinoline moieties –. Compound bearing an isoindoline moiety was synthesized from 4-bromophthalimide through reduction by BH and then protection with (Boc)O. Compound was finally obtained through Suzuki crossing coupling reaction from compound and 3-(hydroxymethyl)phenylboronic acid. The synthesis of acidic components was described in . Three β-substituded phenylpropionic acids including ()-2-(2,3-dihydrobenzofuran-3-yl)acetic acid, 2-phenoxyacetic acid and 3-methyl-3-phenylbutanoic acid, were prepared. ()-Methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate was synthesized from resorcinol via five steps. Treatment of resorcinol with ethyl 4-chloroacetoacetate in the presence of HSO generated compound via Pechmann reaction. Treatment of compound in potassium hydroxide solution, followed by esterification of -OH with acetic anhydride afforded compound . Reduction of under hydrogen atmosphere catalyzed by Pd/C gave key intermediate dihydrobenzofuran . The reaction of the key intermediate with ()-(+)-α-phenylethylamine in the presence of EDCI, TEA and DMAP in DCM resulted in the formation of a pair of diastereoisomers. The desired diastereoisomer was purified via recrystallization from mixed solvents of ethanol and acetone in 31.2% yield. Hydrolysis of compound in the presence of potassium hydroxide and then esterification with methanol gave the final product ()-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate . Ethyl 2-(4-hydroxyphenoxy)acetate was prepared from hydroquinone and ethyl bromoacetate through alkylation. The synthesis of the third acidic component started from isopropylidene malonate . Condensation of isopropylidene malonate with acetone furnished compound , which subsequently underwent Michael addition reaction to generate compound . Treatment of with hydrochloric acid in DMF triggered hydrolyzation and decarboxylation, followed by debenzylation and esterification to give the target compound .