Design,Synthesis And Biological Evaluation Of Non-systemic Intestinal Targeted TGR5 Agonists

TGR5,a membrane-type receptor for bile acids,plays an important role in the control of glucose metabolism,energy homeostasis and inflammation,and has emerged as an intriguing target for the treatment of type 2 diabetes,obesity and related metabolism deseases.However,due to the fact that systemic TGR5 agonists are confronted with many toxic and side effect risks,the non-systemic intestinal targeted TGR5 agonists,which might endow with low toxic and side effects,thus has become one of the research trends of TGR5 agonsit.First,to improve the in vivo activity and reduce the gallbladder side effect of compound A70,and simultaneously to obtain new TGR5 agonists that were applicable to be protected with patent,replacing the bottom phenyl ring of compound A70 with various heteroaryl rings and then a series of new compounds were synthesized.Among this series,the representative compound B5 m displayed significant improved hypoglycemic activity compared with A70 whereas also resulted in serious gallbladder side effect.Meanwhile,keeping the methoxycarbonyl of compounds B5 d and B5 f intact and further replacing their pyridine ring with phenyl ring,and a potential soft drug TY6 was developed,which was rapid metabolized to inactive metabolite in mouse and human serum and exhibited excellent hypoglycemic activity while did not cause gallbladder filling in ICR mice.However,TY6 was flawed with very high systemic exposure and no significant in vivo activity.In order to solve these problems of TY6,many explorations were carried out.First,various kinds of electron-withdrawing groups were introduced to the methyl group of methyl ester to facilitate the hydrolysis of TY6 in serum,but the in vitro potency of these compounds were sharply decreased.Second,we further studied the structure-activity relationship of TY6 and then discovered a more potent potential soft drug C17 b.Finally,lots of stepwise explorations and optimizations were proceeded to reduce the permeability of C17 b,and a series of highly potent target compounds were developed,which were promising for further studies.In addition,we have conducted searches for finding other soft drug groups,but it was demonstrated to be in vain due to the insufficient in vitro activity of these compounds.On the other hand,for the purpose of finding a novel soft drug scaffold,we have built a possible pharmacophore model based on known ligands,and carried out many investigations referring to this model.However,no novel soft drug scaffold meeting with the preliminary requirement of in vitro activity has been discovered.In summary,we have carried out lots of explorations using soft drug strategy and/or non-absorption strategy in order to search for a series of intestinal targeted non-systemic TGR5 agonists,and some progress and achievements have been obtained.Even though no suitable candidate compound has been developed,our study will provide very important information and guidance for the further development of TGR5 agonists.