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Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects.
Lombardo, Matthew; Bender, Kate; London, Clare; Plotkin, Michael A; Kirkland, Melissa; Mane, Joel; Pachanski, Michele; Geissler, Wayne; Cummings, John; Habulihaz, Bahanu; Akiyama, Taro E; Di Salvo, Jerry; Madeira, Maria; Pols, Joanna; Powles, Mary Ann; Finley, Michael F; Johnson, Eric; Roussel, Thomas; Uebele, Victor N; Crespo, Alejandro; Leung, Dennis; Alleyne, Candice; Trusca, Dorina; Lei, Ying; Howard, Andrew D; Ujjainwalla, Feroze; Tata, James R; Sinz, Christopher J.
Affiliation
  • Lombardo M; Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: matthew_lombardo@merck.com.
  • Bender K; Merck & Co., Inc., Kenilworth, NJ, USA.
  • London C; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Plotkin MA; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Kirkland M; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Mane J; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Pachanski M; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Geissler W; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Cummings J; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Habulihaz B; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Akiyama TE; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Di Salvo J; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Madeira M; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Pols J; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Powles MA; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Finley MF; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Johnson E; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Roussel T; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Uebele VN; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Crespo A; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Leung D; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Alleyne C; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Trusca D; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Lei Y; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Howard AD; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Ujjainwalla F; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Tata JR; Merck & Co., Inc., Kenilworth, NJ, USA.
  • Sinz CJ; Merck & Co., Inc., Kenilworth, NJ, USA.
Bioorg Med Chem Lett ; 26(23): 5724-5728, 2016 12 01.
Article in En | MEDLINE | ID: mdl-27815121
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Propionates / Benzofurans / Receptors, G-Protein-Coupled Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2016 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Propionates / Benzofurans / Receptors, G-Protein-Coupled Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2016 Document type: Article