Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects
| Autor: | Christopher Joseph Sinz, Feroze Ujjainwalla, Joel Mane, Eric N. Johnson, John Cummings, Jerry Di Salvo, Michele Pachanski, Michael A. Plotkin, Joanna Pols, Taro E. Akiyama, Andrew D. Howard, Matthew Lombardo, James R. Tata, Maria Madeira, Ying Lei, Wayne M. Geissler, Victor N. Uebele, Michael F.A. Finley, Clare London, Candice Alleyne, Thomas Roussel, Kate Bender, Dennis Leung, Bahanu Habulihaz, Mary Ann Powles, Melissa Kirkland, Dorina Trusca, Alejandro Crespo |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Blood Glucose Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Pharmacology 01 natural sciences Biochemistry Receptors G-Protein-Coupled 03 medical and health sciences chemistry.chemical_compound Mice Pharmacokinetics In vivo Free fatty acid receptor 1 Drug Discovery Potency Animals Humans Hypoglycemic Agents Benzofuran Molecular Biology Benzofurans chemistry.chemical_classification 010405 organic chemistry Organic Chemistry Fatty acid GPR120 0104 chemical sciences High-Throughput Screening Assays 030104 developmental biology Propanoic acid chemistry Diabetes Mellitus Type 2 Molecular Medicine Propionates |
| Zdroj: | Bioorganicmedicinal chemistry letters. 26(23) |
| ISSN: | 1464-3405 |
| Popis: | The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes. |
| Databáze: | OpenAIRE |
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