| Free fatty acid receptor 1(FFAR1,also known as GPR40)is a receptor for medium-to long-chain free fatty acids(FFAs).Mainly expressed in beta cells of pancreatic islets GPR40 can be activated by the endogenous FFAs,which subsequently elicit amplificed glucose-dependent insulin secretion.GPR40 also expressed in the incretin-producing enteroendocrine L cells of the intestinal tract and its activation results in secretion of incretins such as glucagon like peptide 1(GLP-1).Therefore,the profiles of GPR40,regulating glucose homeostasis by two mechanisms,glucosestimulated insulin secretion and incretin secretion,without high risk of hypoglycemia that often associated with existing therapies such as insulin and sulfonylureas make it an excellent target for T2 DM drug development.The most advanced compound TAK-875(Fasiglifam,1)from Takeda was withdrawn from phase III trial due to liver toxicity in 2013.The exact reason for its hepatotoxicity is currently unclear,but GPR40 have rarely no expression in liver,it might be compound related rather than GPR40 related.The clinilcal trail of TAK-875 provided the proof of concept and proved that GPR40 can act as a target for developing antidiabetic drug.In the initial of our work,we focus on the structural exploration of TAK-875.Through introducing of polar atoms or moieties,a series of new compounds were synthesized to improve the polarity and solubility of TAK-875,which all displayed a loss in activity.So,we started to study the GPR40 full agonists.GPR40 full agonists have better ability in insulin secretion and blood glucose regulation for its dual mechanism to activate the GPR40 in enteroendocrine L cells and ? cells of pancreatic islets.LY2881835,the most advanced GPR40 full agonist,finished phase I clinical trial in 2011,possessed high in vivo potency and was easy to synthesis.However,LY2881835 might suffered high clearance,poor stability in vivo and a certain amount of CNS exposure.There,we focused on the structural modification of LY2881835 to generate potent,safe and more stable compound.Preliminary explorations focused on the linker and tail of LY2881835 because the methylene between the phenyl and the piperidyl group and the nonaromatic double bond of the indene in the tail were metabolically susceptible to oxidative metabolism.Through introducing of carbonyl and breaking of the five member ring by two ways,we got two compounds with 4-phenylpiperazine(B9)and 4-benzylpiperazine(B10)as the tail,respectively,which showed improved activity and LM stability compare to LY2881835.We got a compound(B49)with the best activity after a sort of exploration of the phenyl in the tail.B49 possessed improved plasma exposure and prolonged halflife,along with lower CNS exposure.While B49 had 15-times higher distribution to the liver than to plasma and lower distribution to target tissue.So we choose to conduct further exploration due to the safety concerns associated.Furthermore,we continue to explore other agonists with good potent and better safe profiles.We got a series compound with good activity which had fused-ring in the tail.After further exploration of the linker and head,we got another compound with good activity and stability.C22 had two diastereomers G1(S,S-C22)and G2(S,R-C22),which showed minor effect on activity but great difference in PK profiles.G1 and G2 all had decresed CNS exposure than LY2881835.Among them,compound G2 was more favorable for better in vitro activity,LM stability and PK profiles.In addition,G2 had lower exposure in liver than B49,along with better blood exposure and prolonged half-life.While G2 showed much lower glucose lowing effect than LY2881835.The reason for the poorly consistency of the in vitro and in vivo activity and limited ability in maintain the glucose homestasis of G2 in OGTT assay in ICR mice is remain unclear,which need further investigation. |
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