Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects.

@article{Lombardo2016DiscoveryOB,
  title={Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects.},
  author={Matthew Lombardo and Kate Bender and Clare London and Michael A. Plotkin and Melissa E Kirkland and Joel Mane and Michele J Pachanski and Wayne M. Geissler and John C. Cummings and Bahanu Habulihaz and Taro E. Akiyama and Jerry Di Salvo and Maria Isabel A. Madeira and Joanna Pols and Mary Ann Powles and Michael Finley and Eric N Johnson and Thomas Roussel and Victor N. Uebele and Alejandro D Crespo and Dennis H Leung and Candice Alleyne and Dorina Trusca and Ying Lei and Andrew D. Howard and Feroze Ujjainwalla and James R Tata and Christopher J. Sinz},
  journal={Bioorganic & medicinal chemistry letters},
  year={2016},
  volume={26 23},
  pages={5724-5728}
}
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… CONTINUE READING