18 results on '"Free fatty acid receptor 1"'
Search Results
2. Quercetin-3-oleoyl derivatives as new GPR40 agonists: Molecular docking studies and functional evaluation
- Author
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Erika Cione, Maria Cristina Caroleo, Gabriele Carullo, Mariarita Perri, Fabrizio Manetti, and Francesca Aiello
- Subjects
Agonist ,endocrine system ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,GPR40 allosteric site, Insulin secretion, Oleic acid, Quercetin, Type 2 diabetes ,Context (language use) ,01 natural sciences ,Biochemistry ,Partial agonist ,chemistry.chemical_compound ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Humans ,GPR40 allosteric site ,Receptor ,Molecular Biology ,Catechol ,010405 organic chemistry ,Insulin secretion ,Organic Chemistry ,Type 2 diabetes ,Ligand (biochemistry) ,Oleic acid ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,Molecular Medicine ,Quercetin - Abstract
The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1, was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2, was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes.
- Published
- 2019
3. Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs
- Author
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Barbara Pio, Ravi P. Nargund, Yan Guo, Daniel Kosinski, Josien Hubert B, Michael Wright, Michele Pachanski, Harry R. Chobanian, Xiaoping Zhang, Richard Tschirret-Guth, Melissa Kirkland, Andrew D. Howard, Sarah Souza, Eric R. Ashley, Robert K. Orr, Steven L. Colletti, Joel Mane, Jerry Di Salvo, Michael W. Miller, Boonlert Cheewatrakoolpong, Koppara Samuel, William K. Hagmann, James Lamca, Juliann Ehrhart, Maria E. Trujillo, Jackie Shang, Qing Chen, Adam B. Weinglass, and Randal M. Bugianesi
- Subjects
Agonist ,endocrine system ,medicine.drug_class ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Enteroendocrine cell ,01 natural sciences ,Biochemistry ,Receptors, G-Protein-Coupled ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Humans ,Receptor ,Mode of action ,Molecular Biology ,geography ,geography.geographical_feature_category ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Islet ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Mechanism of action ,Drug Design ,Indans ,Molecular Medicine ,medicine.symptom - Abstract
GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.
- Published
- 2019
4. Design, synthesis and biological activity of deuterium-based FFA1 agonists with improved pharmacokinetic profiles
- Author
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Xiaohua Zeng, Ruoxian Liao, Haidong Chen, Zheng Li, Luyong Zhang, Bing Liu, Yuyi Li, Fengjian Deng, and Liming Deng
- Subjects
Agonist ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Phenylpropanoic acid ,01 natural sciences ,Biochemistry ,Receptors, G-Protein-Coupled ,Glibenclamide ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pharmacokinetics ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Humans ,Moiety ,Binding site ,Molecular Biology ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Biological activity ,Deuterium ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,medicine.drug - Abstract
The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound 2 is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available analogs, we tried to block the route of β-oxidation by incorporating deuterium at phenylpropionic acid moiety. As expected, the deuterium-based analogs 3 and 4 exhibited better pharmacokinetic properties than parent compound 2. Although the difference of potency between compound 2 and 3 is quite small, the glucose-lowering effect of deuterium analog 3 was better than that of compound 2. Meanwhile, compound 3 docked well into the same binding pocket of TAK-875, and formed almost identical interactions of TAK-875 in binding site. Different from glibenclamide, a lower risk of hypoglycemia was observed in compound 3 even at the high dose of 60 mg/kg.
- Published
- 2019
5. Synthesis, biological evaluation, and molecular docking investigation of benzhydrol- and indole-based dual PPAR-γ/FFAR1 agonists
- Author
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Mohamed A. Helal, Mohamed Gomaa, Khaled M. Darwish, Samia M. Mostafa, Ismail Salama, and El-Sayed Khafagy
- Subjects
0301 basic medicine ,Indoles ,medicine.drug_class ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,01 natural sciences ,Biochemistry ,Receptors, G-Protein-Coupled ,Structure-Activity Relationship ,03 medical and health sciences ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Humans ,Benzhydryl Compounds ,Thiazolidinedione ,Receptor ,Molecular Biology ,G protein-coupled receptor ,Indole test ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Insulin ,Organic Chemistry ,0104 chemical sciences ,Molecular Docking Simulation ,PPAR gamma ,030104 developmental biology ,Molecular Medicine ,Rosiglitazone ,medicine.drug - Abstract
Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue.
- Published
- 2018
6. Discovery of N -arylpyrroles as agonists of GPR120 for the treatment of type II diabetes
- Author
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Zhihua Sui, William V. Murray, Celia Jenkinson, Norman D. Huebert, Peter Haug, Michael P. Winters, Wen Yan, James N. Leonard, Yuanping Wang, Arthur T. Suckow, Austin Bell, Tatiana Koudriakova, Hong Hua, Wilmelenne Clapper, Wall Mark, and Joseph Gunnet
- Subjects
0301 basic medicine ,Agonist ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Type 2 diabetes ,Pharmacology ,Biochemistry ,Diabetes Mellitus, Experimental ,Receptors, G-Protein-Coupled ,Type ii diabetes ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Pyrroles ,Receptor ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,GPR120 ,medicine.disease ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,030220 oncology & carcinogenesis ,Molecular Medicine ,Selectivity ,Lead compound - Abstract
The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.
- Published
- 2018
7. Discovery of a novel potent GPR40 full agonist
- Author
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Eric Arnoult, Meghan Hall, Monicah A. Otieno, Hui Huang, Tonya Martin, Jose Silva, Joe Gunnet, Jianying Liu, Yuanping Wang, Shuyuan Zhao, Sanath K. Meegalla, June Xu, Alessandro Pocai, Mark R. Player, Brian Rady, and S. Paul Lee
- Subjects
0301 basic medicine ,Agonist ,endocrine system ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Stimulation ,CHO Cells ,Pharmacology ,Biochemistry ,Glucagon-Like Peptide-1 Receptor ,Receptors, G-Protein-Coupled ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Cricetulus ,Dogs ,Glucuronides ,Piperidines ,In vivo ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Sulfones ,Receptor ,Molecular Biology ,Benzofurans ,G protein-coupled receptor ,Glucose lowering ,Molecular Structure ,Phenylpropionates ,Chemistry ,Biphenyl Compounds ,Organic Chemistry ,In vitro ,Rats ,Molecular Docking Simulation ,Macaca fascicularis ,Pyrimidines ,030104 developmental biology ,Pyrazines ,Microsomes, Liver ,Molecular Medicine - Abstract
Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.
- Published
- 2018
8. FFAR1/GPR40: One target, different binding sites, many agonists, no drugs, but a continuous and unprofitable tug-of-war between ligand lipophilicity, activity, and toxicity
- Author
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Erika Cione, Gabriele Carullo, Maria Cristina Caroleo, Francesca Aiello, Fabrizio Manetti, and Paolo Governa
- Subjects
Liver toxicity ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,FFAR1/GPR40 ,Pharmacology ,Ligands ,01 natural sciences ,Biochemistry ,Receptors, G-Protein-Coupled ,Drug Development ,Free fatty acid receptor 1 ,Type 2 diabetes mellitus ,Drug Discovery ,Humans ,Hypoglycemic Agents ,Binding site ,Molecular Biology ,TAK-875 ,Binding Sites ,010405 organic chemistry ,Chemistry ,Ligand ,Organic Chemistry ,Type 2 Diabetes Mellitus ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Lipophilicity ,Toxicity ,Molecular Medicine ,FFAR1/GPR40, Allosteric agonists, Type 2 diabetes mellitus, TAK-875 ,Allosteric agonists - Abstract
The progress made so far in the elucidation of the structure of free fatty acid receptor 1 (FFAR1) and its secondary and ternary complexes with partial and full allosteric ligands led to the discovery of various putative binding regions on the FFAR1 surface. Attempts to develop FFAR1 agonists culminated with the identification of TAK-875 (1), whose phase 3 clinical trials were terminated due to potential liver toxicity. In the search of safer agonists, numerous classes of new compounds were designed, synthesized, and tested. Chemical decoration of the scaffolds was rationalized to reach a good balance between lipophilicity, activity, and toxicity. Today, targeting FFAR1 with positive modulators represents an attractive pharmacological tool for the treatment of type 2 diabetes mellitus (T2DM), mainly because of the lack of hypoglycaemic side effects associated with several antidiabetic drugs currently available. Moreover, considering the involvement of FFAR1 in many physio-pathological processes, its agonists are also emerging as possible therapeutic tools for alleviating organ inflammation and fibrosis, as well as for the treatment of CNS disorders, such as Alzheimer's disease and dementia.
- Published
- 2021
9. GPR40 agonists for the treatment of type 2 diabetes mellitus: The biological characteristics and the chemical space
- Author
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Cheng Chen, Ya-Qiu Long, and He Li
- Subjects
Models, Molecular ,0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Clinical Biochemistry ,Pharmaceutical Science ,Incretin ,Enteroendocrine cell ,Type 2 diabetes ,Pharmacology ,Hypoglycemia ,Biochemistry ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Free fatty acid receptor 1 ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Secretion ,Molecular Targeted Therapy ,Sulfones ,Molecular Biology ,Benzofurans ,Chemistry ,Organic Chemistry ,Type 2 Diabetes Mellitus ,medicine.disease ,Druglikeness ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Molecular Medicine - Abstract
GPR40 belongs to the GPCR family and the activation of GPR40 has been shown to induce glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells as well as incretin secretion from intestinal endocrine cells. Therefore, GPR40 has emerged as a viable and promising therapeutic target for type 2 diabetes mellitus (T2DM) without the risk of hypoglycemia. However, the termination of TAK-875 in phase III clinical trials for the hepatotoxicity issue threw doubt over the long-term safety of targeting GPR40. Herein, we summarized the newly disclosed biological characteristics and the druglikeness-based structural evolution of GPR40 agonists to advance the development of GPR40-based anti-diabetic drugs.
- Published
- 2016
10. Discovery of the imidazole-derived GPR40 agonist AM-3189
- Author
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Jian Luo, Jinqian Liu, Jane Zhang, Jonathan B. Houze, Todd J. Kohn, Run Zhuang, Simon Wong, Michael D. Bartberger, Zhihua Ma, Daniel C.-H. Lin, Yingcai Wang, George Tonn, Jiwen Jim Liu, Frank Li, Liusheng Zhu, An-Rong Li, Julio C. Medina, and Rajiv Sharma
- Subjects
0301 basic medicine ,Agonist ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Receptors, G-Protein-Coupled ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,Pharmacokinetics ,In vivo ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Animals ,Humans ,Imidazole ,Structure–activity relationship ,Molecular Biology ,G protein-coupled receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Drug discovery ,Organic Chemistry ,Imidazoles ,Rats ,Macaca fascicularis ,030104 developmental biology ,Molecular Medicine - Abstract
As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.
- Published
- 2016
11. Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40)
- Author
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Vasyl S. Naumchyk, Yuri Kheylik, Sergey Zozulya, Ivan S. Kondratov, M. O. Platonov, Ihor Zahanich, and Mikhail Krasavin
- Subjects
Membrane permeability ,Clinical Biochemistry ,Pharmaceutical Science ,Plasma protein binding ,Biochemistry ,Receptors, G-Protein-Coupled ,Methylamines ,Mice ,Structure-Activity Relationship ,Cytochrome P-450 Enzyme System ,Free fatty acid receptor 1 ,Drug Discovery ,Aqueous solubility ,medicine ,Animals ,Humans ,Protein Isoforms ,Potency ,Oxazoles ,Molecular Biology ,ADME ,Oxadiazoles ,Binding Sites ,Chemistry ,Organic Chemistry ,Combinatorial chemistry ,Protein Structure, Tertiary ,Molecular Docking Simulation ,Mechanism of action ,Microsome ,Molecular Medicine ,Caco-2 Cells ,Propionates ,medicine.symptom ,Half-Life ,Protein Binding - Abstract
A screening hit that showed a weak (EC50 = 18 μM), partial agonistic effect on GPR40 was used a prototype for expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles and 1,2,4-oxadiazoles with significantly improved potency (best EC50 = 0.058 μM). The lead compounds in each chemotype showed a very good ADME profile (aqueous solubility, plasma protein binding, microsomal stability and membrane permeability) and no appreciable inhibition of key cytochromes P450. The compounds reported are significant new starting points for further preclinical development of future diabetic agents with a mechanism of action for which a first-in-class agent is yet to be approved.
- Published
- 2015
12. Recent developments in the discovery of FFA1 receptor agonists as novel oral treatment for type 2 diabetes mellitus
- Author
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Michael Wagner and Elisabeth Defossa
- Subjects
Molecular Structure ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Incretin ,Type 2 Diabetes Mellitus ,Enteroendocrine cell ,Type 2 diabetes ,Pharmacology ,medicine.disease ,Biochemistry ,Receptors, G-Protein-Coupled ,Diabetes Mellitus, Type 2 ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Humans ,Hypoglycemic Agents ,Molecular Medicine ,Receptor ,Molecular Biology ,Glycemic ,G protein-coupled receptor - Abstract
Despite the availability of established medication for treatment of type 2 diabetes mellitus (T2DM) there still remains a significant unmet need for new effective, oral antidiabetic agents that improve glycemic control while maintaining an excellent safety profile. In this regard the FFA1 receptor has emerged as an attractive target in recent years. Activation of the FFA1 receptor has been shown to not only amplify glucose induced insulin secretion from pancreatic beta cells but also to stimulate incretin secretion from intestinal endocrine cells. The current review highlights on the latest developments and clinical data from evolving research on the potential of FFA1 agonists as effective treatment for T2DM.
- Published
- 2014
13. Discovery of novel orally bioavailable GPR40 agonists
- Author
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Qiyue Hu, Yang Fanglong, Lei Zhang, Dong Qing, Hongbo Fei, Jun Feng, Piaoyang Sun, Jijun Yuan, Suxin Zheng, and Hejun Lu
- Subjects
Models, Molecular ,Agonist ,endocrine system ,medicine.drug_class ,medicine.medical_treatment ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Receptors, G-Protein-Coupled ,Small Molecule Libraries ,Mice ,Structure-Activity Relationship ,Dogs ,In vivo ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Animals ,Humans ,Sulfones ,Molecular Biology ,Benzofurans ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Insulin ,Organic Chemistry ,Macaca mulatta ,Rats ,Bioavailability ,Disease Models, Animal ,Diabetes Mellitus, Type 2 ,Molecular Medicine ,Secretagogue - Abstract
The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys.
- Published
- 2013
14. AMG 837: A potent, orally bioavailable GPR40 agonist
- Author
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Jenny Ying-Lin Lu, Jonathan B. Houze, Rajiv Sharma, Michael J. Schmitt, Jeff D. Reagan, Kathy Nguyen, Hui Tian, Ying Sun, Jinqian Liu, Yang Li, Daniel C.-H. Lin, Liang Tang, Wei Qiu, Michael Chen, Steven J. Shuttleworth, Yingcai Wang, Alex Zhang, George Tonn, Edwin Lopez, Jiwen Liu, Michelle Akerman, Julio C. Medina, Liusheng Zhu, Jian Luo, and Jane Zhang
- Subjects
Agonist ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Clinical Biochemistry ,Administration, Oral ,Biological Availability ,Pharmaceutical Science ,Stimulation ,Pharmacology ,Biochemistry ,Receptors, G-Protein-Coupled ,Mice ,Structure-Activity Relationship ,Internal medicine ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Animals ,Receptor ,Molecular Biology ,G protein-coupled receptor ,Mice, Knockout ,Orphan receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Insulin ,Biphenyl Compounds ,Organic Chemistry ,Stereoisomerism ,Endocrinology ,Molecular Medicine ,Secretagogue - Abstract
The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.
- Published
- 2012
15. Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists
- Author
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Aleksandr Petrov, Lihu Yang, Ralph T. Mosley, Carina P. Tan, George J. Eiermann, Joel P. Berger, Sanjeev Kumar, Peter T. Meinke, Eric Chang, Sander G. Mills, Nancy A. Thornberry, Cheng Tang, Monica Einstein, Eric Cline, Yun-Ping Zhou, Min Ge, Songnian Lin, Andrew D. Howard, Yue Feng, Changyou Zhou, Taro E. Akiyama, and Gino Salituro
- Subjects
Agonist ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Receptors, G-Protein-Coupled ,Mice ,Structure-Activity Relationship ,Pharmacokinetics ,Oral administration ,Internal medicine ,Free fatty acid receptor 1 ,Diabetes mellitus ,Drug Discovery ,medicine ,Animals ,Molecular Biology ,Pancreatic hormone ,Mice, Knockout ,Glucose tolerance test ,medicine.diagnostic_test ,Chemistry ,Insulin ,Organic Chemistry ,medicine.disease ,Endocrinology ,Molecular Medicine ,Thiazolidinediones ,Protein Binding - Abstract
Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
- Published
- 2010
16. Synthesis and SAR of 1,2,3,4-tetrahydroisoquinolin-1-ones as novel G-protein-coupled receptor 40 (GPR40) antagonists
- Author
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David W. Piotrowski, Bruce M. Bechle, Paul D. Bonin, David D. Boyer, Shawn D. Doran, Gayatri Balan, Richard K. Frisbie, Paul S. Humphries, Walter C. Soeller, James A. Southers, Robert M. Oliver, John William Benbow, Xiaojing Yang, Kenneth J. DiRico, and Edward L. Conn
- Subjects
Metabolic Clearance Rate ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmaceutical Science ,Ligands ,Inhibitory postsynaptic potential ,Biochemistry ,Receptors, G-Protein-Coupled ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Pharmacokinetics ,In vivo ,Tetrahydroisoquinolines ,Free fatty acid receptor 1 ,Drug Discovery ,Animals ,Humans ,Receptor ,Molecular Biology ,G protein-coupled receptor ,Chemistry ,Organic Chemistry ,In vitro ,Rats ,Models, Chemical ,Drug Design ,Microsome ,Molecular Medicine - Abstract
The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein-coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is reported.
- Published
- 2009
17. Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists
- Author
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Arun Balakrishnan, Asha Kulkarni-Almeida, Shaila Srinivasan, Rajendra Joshi, Atish Rodge, Sarala Balachandran, Sandip B. Bharate, Sudhir Kumar, Ram A. Vishwakarma, and Jaspreet Kaur
- Subjects
Agonist ,endocrine system ,medicine.drug_class ,Stereochemistry ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Pharmaceutical Science ,CHO Cells ,Phloroglucinol ,Ligands ,Biochemistry ,Chemical synthesis ,Receptors, G-Protein-Coupled ,Cricetulus ,Cricetinae ,Free fatty acid receptor 1 ,Drug Discovery ,medicine ,Agonistic behaviour ,Animals ,Humans ,Molecular Biology ,G protein-coupled receptor ,biology ,Chemistry ,Fatty Acids ,Organic Chemistry ,Biological activity ,biology.organism_classification ,In vitro ,Rats ,Diabetes Mellitus, Type 2 ,Models, Chemical ,Drug Design ,Molecular Medicine ,Calcium - Abstract
In this letter, we report discovery of diacylphloroglucinol compounds as a new class of GPR40 (FFAR1) agonists. Several diacylphloroglucinols with varying length of acyl functionality and substitution on aromatic hydroxyls were synthesized and evaluated for GPR40 agonism using functional calcium-flux assay. Out of 17 compounds evaluated, 14, 17, 19 and 25 exhibited good GPR40 agonistic activity with EC(50) values ranging from 0.07 to 8 microM (pEC(50) 7.12-5.09), respectively, with maximal agonistic response of 84-102%.
- Published
- 2008
18. Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor
- Author
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Stephen C. McKeown, Thomas R. Littleton, Andrew J. Peat, Steve P. Watson, Aaron S. Goetz, Deirdre Mary Bernadette Hickey, David F. Corbett, Celia P. Briscoe, and Eric C. Bigham
- Subjects
endocrine system ,Chemical Phenomena ,Stereochemistry ,High-throughput screening ,Carboxylic acid ,Clinical Biochemistry ,Carboxylic Acids ,Drug Evaluation, Preclinical ,Biological Availability ,Pharmaceutical Science ,CHO Cells ,Ligands ,Biochemistry ,Chemical synthesis ,Receptors, G-Protein-Coupled ,Structure-Activity Relationship ,Cricetulus ,Solid-phase synthesis ,Cricetinae ,Free fatty acid receptor 1 ,Drug Discovery ,Animals ,Molecule ,Molecular Biology ,chemistry.chemical_classification ,Chemistry, Physical ,Ligand ,Organic Chemistry ,Small molecule ,Rats ,chemistry ,Molecular Medicine ,Indicators and Reagents ,Protein Binding - Abstract
The discovery, synthesis and structure-activity relationship (SAR) of novel carboxylic acid agonists for GPR40 are described. Aryl propionic acid 1, identified from a high throughput screen, was selected for chemical exploration. Compound 2 was identified as our lead molecule through efficient solid phase combinatorial array chemistry and had an attractive in vitro and in vivo pharmacokinetic profile in rat. These ligands may prove useful in establishing a role for GPR40 in insulin regulation.
- Published
- 2007
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