| Diabetes mellitus is a chronic metabolic disease which is characterized by high level of blood sugar. Type 2 diabetes mellitus (T2DM) accounts for almost 90% of all cases of diabetes in the world. In our country, diabetes have a high incidence. As predicted by International Diabetes Federation (IDF) in 2013, China has the largest diabetes population in the world with 98 million. Unfortunately, existing antidiabetic agents, such as sulfonylureas and biguanides could hardly be used to cure or even prevent progression of the disease, and often have adverse effects such as hypoglycemia, weigh gain and gastrointestinal disorders. Therefore, the development of novel antidiabetic drugs is of urgent need.Glucagons like peptide (GLP)-1 is an incretin hormone. Studies show that after several minutes of human intakes food, intestines are stimulated to produce GLP-1 into blood to promote glucose-dependent insulin’s secretion, thereby lowering the level of blood sugar. However, GLP-1 can be decomposed rapidly by dipeptidyl peptidase IV (DPP-IV), with very short half-life (ti/2= 1-2 min). Therefore, Inhibition of DPP-IV can prolong the half-life of GLP-1 and enhance the activity of incretins that play an important role in insulin secretion and blood glucose control regulation. Accordingly, small molecule DPP-IV inhibitors has been a topic of intense interest.Linagliptin that was marketed in 2011 is a DPP-IV inhibitor with good efficacy and safety. It is a non-peptide DPP-IV inhibitor which uses 3-methyl-3,7-dihydro-purine-2,6-dione (Xanthine) as the scaffold. Based on molecular docking, the N-1 butyne occupies the S1 hydrophobic pocket of DPP-IV; C-6 carbonyl group of xanthine scaffold forms hydrogen bond with Tyr631; aromatic stacking interactions are formed between the Xanthine ring system and Tyr547 as well as between the quinazoline ring and Trp629; The hydrogen bond network is formed by the amino function on the piperidine ring with acceptor groups on the protein Glu205, Glu206 and Tyr662. In 2012, Ikuma et al reported that compounds with carboxylic group can greatly improve the DPP-IV inhibitory activity. This is a class of 3H-imidazo[4,5-c]quinolin as the basic nucleus compound. In terms of molecular docking, the carboxylic acids on the benzene can form the hydrogen bond with Lys554, which can significantly improve the biological activity.With the above-mentioned information in mind and by using Xanthine as a basic skeleton, we designed and synthesized 22 compounds Al-16 and Bl-6 having N-1 carboxylic group and N-7 2-chloro/cyanobenzyl groups, using bioisosterism and hybrid pharmacophore. All the target compounds were characterized by 13C-NMR, 1H-NMR and ESI-MS spectra. Then, we tested the in vitro bioactivities of compounds Al-16 and B1-6 with Sitagliptin as a positive control. The results shows that, all the compounds exhibited certain DPP-IV inhibitory activities. In particular, compounds A2, A4, A9, A13, B3 and B5 showed the good activities. Among them, compound A13 exhibited the highest activity (IC50=36±2 nM). Preliminary structure-activity relationships show that:Firstly, all the compounds having 2-chlorobenzyl groups at the N-7 position, that is, compounds Al, A2, A4, A7, A9, All, A13 and A15, exhibited significantly higher inhibitory activities than their corresponding analogs having a 2-cyanobenzyl group, that is, compounds A3, A6,5, A8, A10, A12, A14 and A16.Secondly, introduction of one carboxylic group on the N-1 phenyl substituents, on going from compound A15 to A1 (or A4), led to an increase in the inhibitory activity. However, introduction of one more carboxylic group does not certainly lead to an increase in the inhibitory activity, as shown by compound A6 that exhibited slightly lower activity than compound A5.Thirdly, the position of carboxylic group on the N-1 benzyl substituents has significant impact on the inhibitory activity. It is clear that the compounds having a 3-carboxylic group on the N-1 benzyl group (i.e., compounds A4, A5, A9, A10, A13 and A14), exhibited higher inhibitory activity than their corresponding analogs having a 4-carboxylic group (i.e., compounds Al, A3, A7, A8, All and A12). For the series having a 3-carboxylic group, an electron-donating group at the 4-position, such as methoxy group (i.e., compound A13), is more favorable than an electron-withdrawing group, such as F (i.e., compound A9).Fourthly, compounds with N-1 pyridyl substituents generally shows the higher activity than the compounds with N-1 phenyl substituents, such as B5> A4, B6> A5 and B1>A1.Fifth, introduction of 2-carboxylic group (or 3-carboxylic group) on the N-1 pyridyl substituents, such as B3 and B4 (or B5 and B6), exhibited higher inhibitory activity than 4-carboxylic group on N-1 pyridyl substituents, such as Bl and B2. This law is similar to third law, suggests us that no matter benzyl or pyridyl substituent on N-1, the inhibitory activity of compounds would be impove when the carboxylic group on the ortho-or meta-position of benzyl (or pyridyl) relative to Xanthine.The present finding suggests that introduction of a carboxylic group into the Xanthine structure would lead to a large enhancement in the DDP-IV inhibitory activity. Taken together, the above-mentioned results suggest that one compound having both 3-carboxylic and electron-donating substituents on the N-1 benzyl group, while having a 2-chlorobenzyl group at the N-7 position, for example, A13 showed strong inhibitory activity. This preliminary structure-activity relationship may provide useful guidance for future rational design of Xanthine analogs having potent inhibitory activities toward DDP-IV. |
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