Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists
| Autor: | Richard Hughes, Guiqing Liang, Jeffrey Shapiro, Zhao Yan, Rishi K. Jain, Sarah J. Luchansky, Luis Llamas, Vidya Kunjathoor, Jill Nunez, Stefan Peukert, Michael Pietropaolo, Avirup Bose, Xiaoping Wu, Adam Carlson, Anja Castellana, Guo He |
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| Rok vydání: | 2014 |
| Předmět: |
Agonist
Oral treatment medicine.medical_specialty Ligand efficiency business.industry medicine.drug_class Phenotypic screening Organic Chemistry Antidiabetic treatment Pharmacology Biochemistry Bioavailability Endocrinology Pharmacokinetics Internal medicine Drug Discovery Medicine business Receptor |
| Zdroj: | ACS Medicinal Chemistry Letters. 5:1114-1118 |
| ISSN: | 1948-5875 |
| Popis: | The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels. |
| Databáze: | OpenAIRE |
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