Design,Synthesis And The SAR Study Of Novel GPR40 Agonists

Diabetes mellitus is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period and can cause a variety of complications that seriously endanger human health.Type 2 diabetes is the most common type of diabetes,whose feature is insulin resistance or insulin secretion deficiency leading to hyperglycemia,accounting for about 80%of the total number of diabetic cases.Currently,people with type 2 diabetes mainly treated with oral or injected hypoglycemic agents to improve glycaemic control.Since diabetes is a chronic progressive disease,it takes long-term medication to control blood glucose,and the development of safer and more effective new hypoglycemic agents remains an urgent need for patients.GPR40,also known as the free fatty acid 1?FFA1?receptor,is a G-protein coupled receptor with a classical seven transmembrane structure.Activation of GPR40 induce glucose-stimulated insulin secretion,thereby greatly reducing the risk of inducing hypoglycemia,and its agonists have also shown strong hypoglycemic effects in preclinical and clinical trials.However,the most advanced GPR40 agonist TAK-875 was terminated in Phase III clinical trials due to the concern of liver toxicity.Thus,the drug discovery of GPR40 need more chemical structure diversity and pharmacology toxicology studies.This dissertation mainly focuses on the problems that most GPR40 agonists are in high lipophilicity and may cause side effects such as lipotoxicity and off-targeting effect.And we aimed to design and discover novel GPR0 agonists with improving activity and selectivity,reducing lipophilicity,and increasing metabolic stability.Through the structural analysis of a large number of GPR40 agonists reported in the literature and patents,the pharmacophore model of GPR40 agonists can be basically divided into three parts:the phenylpropionic acid head,the linker chain,and the aromatic fragment tail.Based on the pharmacophore model,we intended to two strategies,namely bioisosteric replacement and conformation constraint,to modify the reported agonists,aiming to abtain GPR40 agonists with new structures,high potency,high selectivity and low lipophilicity.On the one hand,we used the newly discovered GPR40 full agonist 1-65 as a lead compound in our research group to try to replace the core five-membered aromatic rings with bioisosteresis to increase activity,metabolic stability and the polarity.The experimental results show that when the core thiophene ring is replaced with a thiazole ring or a benzothiazole ring,the obtained compounds 2-1 and 2-5 showed submicromolar activity.Next,starting from compounds 2-5,compounds that introducing polar aromatic or?-substitutions have reduced or completely lost activity.Further,when the length of the linking chain of the compound was examined,it was found that compounds having only one oxygen atom as the linker chain showed higher activity,and the maximum potency was also improved as compared to 2-5.After systematic study of the structure-activity relationship,the GPR40 agonist 2-33 was found to have high agonistic activity and potency.On the other hand,we also attempted to increase the steric hindrance of the carboxylic acid side chain through conformation constraints to improve the selectivity of the molecules.First,based on the methodology derived from the structure of artemisinin hydrolysate,previously developed by our research group,combined with the privileged structures of reported GPR40 agonists,a series of unique hydroquinoline GPR40 agonists was designed and synthesized.In addition,based on the GPR40 full agonist 1-64 containing the pyrrolidine structure reported by Bristol-Myers Squibb,we used a skeleton transition strategy to design and synthesize another class of conformationally constrained molecules.Through the conformation constraint strategy,we have obtained several GPR40 agonists with medium agonistic activity and highly transforming potential,such as 2-41 and 2-45.Finally,we tested the pharmacokinetic properties of compound 2-33 in rats.After oral administration,2-33 was absorbed rapidly in vivo,with a T_max of 0.5 h,a half-life of 2.2 h,and an oral bioavailability of 39.3%.Therefore,we successfully improved the metabolic stability of the compound by modifying the structure of the core thiophene ring of the full agonist 1-65,which also provide valuable information for the future research of GPR40 agonists.