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Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Dec 01; Vol. 26 (23), pp. 5724-5728. Date of Electronic Publication: 2016 Oct 24. - Publication Year :
- 2016
-
Abstract
- 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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Benzofurans blood
Blood Glucose analysis
Blood Glucose metabolism
Diabetes Mellitus, Type 2 blood
Diabetes Mellitus, Type 2 drug therapy
Diabetes Mellitus, Type 2 metabolism
Drug Evaluation, Preclinical
High-Throughput Screening Assays
Humans
Hypoglycemic Agents blood
Hypoglycemic Agents chemistry
Hypoglycemic Agents pharmacology
Mice
Propionates blood
Receptors, G-Protein-Coupled metabolism
Benzofurans chemistry
Benzofurans pharmacology
Propionates chemistry
Propionates pharmacology
Receptors, G-Protein-Coupled agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 26
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 27815121
- Full Text :
- https://doi.org/10.1016/j.bmcl.2016.10.054