ABSTRACT
Type 2 diabetes mellitus (T2DM) is a lifelong disease that requires long-term medication to control glucose levels, and thereby long-acting drug has been clinically needed for improving medical adherence. The free fatty acid receptor 1 (FFA1) was considered as a promising target for several diseases, such as T2DM, pain and fatty liver. However, no once-weekly FFA1 agonist has been reported until now. Herein, we report the successful discovery of ZLY50, the first once-weekly FFA1 agonist with a completely new chemotype, highly agonistic activity and selectivity on FFA1. Moreover, ZLY50 has enough brain exposure to activate FFA1 in brain, and it is the first orally available FFA1 agonist with analgesic activity. Notably, the long-term anti-diabetic and anti-fatty liver effects of ZLY50 (once-weekly) were better than those of HWL-088 (once-daily), a highly potent FFA1 agonist with far stronger glucose-lowering effect than Phase 3 clinical candidate TAK-875. Further mechanism studies suggested that ZLY50 alleviates fatty liver by regulating the expressions of genes related to lipid metabolism, mitochondrial function, and oxidative stress in liver.
Subject(s)
Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Receptors, G-Protein-Coupled , Humans , Diabetes Mellitus, Type 2/drug therapy , Glucose Tolerance Test , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Receptors, G-Protein-Coupled/agonists , Blood Glucose/drug effects , Drug Discovery , Delayed-Action PreparationsABSTRACT
FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic ß cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo [b][1,4]dioxin-2-yl)methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation.
Subject(s)
Dioxanes/pharmacology , Hypoglycemic Agents/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Blood Glucose/drug effects , Dioxanes/chemical synthesis , Dioxanes/pharmacokinetics , HEK293 Cells , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Mice, Inbred ICR , Molecular Structure , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The free fatty acid receptor 1 (FFA1/GPR40) has attracted extensive attention as a novel antidiabetic target. Aiming to explore the chemical space of FFA1 agonists, a new series of lead compounds with amide linker were designed and synthesized by combining the scaffolds of NIH screened lead compound 1 and GW9508. Among them, the optimal lead compound 17 exhibited a considerable agonistic activity (45.78%) compared to the NIH screened compound 1 (15.32%). During OGTT in normal mice, the compound 17 revealed a significant glucose-lowering effect (-23.7%) at the dose of 50mg/kg, proximity to the hypoglycemic effect (-27.8%) of Metformin (200mg/kg). In addition, the compound 17 (100mg/kg) also exhibited a significant improvement in glucose tolerance with a 29.1% reduction of glucose AUC0-2h in type 2 diabetic mice. All of these results indicated that compound 17 was considered to be a promising lead structure suitable for further optimization.
Subject(s)
Amides/chemistry , Fatty Acids, Nonesterified/agonists , Animals , Area Under Curve , Blood Glucose/analysis , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glucose Tolerance Test , Mice , Structure-Activity RelationshipABSTRACT
The free fatty acid receptor 1 (FFA1/GPR40) is a novel antidiabetic target based on particular mechanism in enhancing glucose-stimulated insulin secretion. Most of reported FFA1 agonists, however, have been suffered from relatively high lipophilicity and molecular weight. Aiming to develop potent agonists with improved physicochemical property, 25 compounds containing triazole scaffold and various carboxylic acid fragments were synthesized via the click chemistry. Among them, the optimal lead compound 26 with relatively low lipophicity (LogD7.4=1.95) and molecular weight (Mw = 391.78) exhibited a considerable FFA1 agonistic activity (36.15%). In addition, compound 26 revealed a significant improvement in the glucose tolerance with a 21.4% and 14.2% reduction of glucose AUC0-2h in normal ICR mice and type 2 diabetic C57BL/6 mice, respectively. All of these results demonstrated that compound 26 was considered to be a promising lead compound suitable for further optimization.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Hypoglycemic Agents/pharmacology , Receptors, G-Protein-Coupled/agonists , Triazoles/pharmacology , Animals , Blood Glucose/drug effects , Click Chemistry , Dose-Response Relationship, Drug , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Hypoglycemic Agents/pharmacology , Receptors, G-Protein-Coupled/agonists , Thiazoles/pharmacology , Animals , Blood Glucose/drug effects , CHO Cells , Cricetulus , Dose-Response Relationship, Drug , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The free fatty acid receptor 1 (FFA1) has gained significant interest as a novel antidiabetic target. Most of FFA1 agonists reported in the literature bearing a common biphenyl scaffold, which was crucial for toxicity verified by the researchers of Daiichi Sankyo. Herein, we describe the systematic exploration of non-biphenyl scaffold and further chemical modification of the optimal pyrrole scaffold. All of these efforts led to the identification of compound 11 as a potent and orally bioavailable FFA1 agonist without the risk of hypoglycemia. Further molecular modeling studies promoted the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Pyrroles/chemistry , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Drug Discovery , Glucose Tolerance Test , Male , Mice , Mice, Inbred ICR , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg.
Subject(s)
Acetates/chemistry , Drug Design , Hypoglycemic Agents/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Acetates/chemical synthesis , Acetates/therapeutic use , Animals , Binding Sites , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Diabetes Mellitus, Type 2/drug therapy , Glucose Tolerance Test , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Molecular Docking Simulation , Protein Structure, Tertiary , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice.
Subject(s)
Acetanilides/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Receptors, G-Protein-Coupled/agonists , Acetanilides/chemical synthesis , Acetanilides/chemistry , Animals , CHO Cells , Cricetulus , Dose-Response Relationship, Drug , Humans , Male , Mice, Inbred C57BL , Mice, Inbred ICR , Molecular Structure , Structure-Activity RelationshipABSTRACT
Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic ß-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50=62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.
Subject(s)
Acetates/chemical synthesis , Acetates/pharmacology , Receptors, G-Protein-Coupled/agonists , Acetates/chemistry , Acetates/pharmacokinetics , Animals , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Models, Molecular , Rats , Receptors, G-Protein-Coupled/chemistry , Structure-Activity RelationshipABSTRACT
Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic ß-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing.