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

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• 作者：Matthew Lombardo ; ^{matthew_lombardo@merck.com" class="auth_mail" title="E-mail the corresponding author} ; Kate Bender ; Clare London ; Melissa Kirkland ; Joel Mane ; Michele Pachanski ; Wayne Geissler ; John Cummings ; Bahanu Habulihaz ; Taro E. Akiyama ; Jerry Di Salvo ; Maria Madeira ; Joanna Pols ; Mary Ann Powles ; Michael F. Finley ; Eric Johnson ; Thomas Roussel ; Victor N. Uebele ; Alejandro Crespo ; Dennis Leung ; Candice Alleyne ; Dorina Trusca ; Ying Lei ; Andrew D. Howard ; Feroze Ujjainwalla ; James R. Tata ; Christopher J. Sinz
• 关键词：GPR120 ; FFAR4 ; Aryloxybutanoic acid ; Benzofuran propanoic acid ; Type 2 diabetes ; Ultra high-throughput screening
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：26
• 期：23
• 页码：5724-5728
• 全文大小：1188 K

文摘

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.