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Discovery of 7-(Pyridin-3-yl)thieno[3,2-]pyridine-5-carboxamides as Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Authors

Henderson SH Scott H , Ringuette AE Anna E , Whomble DL David L , Capstick RA Rory A , Richardson AE Alexa E , Maurer MA Mallory A , Billard NB Natasha B , Lei X Xia , Wilkinson JC Joshua C , Kethanapalli SH Sri H , Cho HP Hyekyung P , Rodriguez AL Alice L , Niswender CM Colleen M , Peng W Weimin , Rook JM Jerri M , Chang S Sichen , Blobaum AL Anna L , Boutaud O Olivier , Felts AS Andrew S , Conn PJ P Jeffrey , Lindsley CW Craig W , Temple KJ Kayla J .
ACS chemical neuroscience. 2026 01 25; 17(3).
610-623

Abstract

Herein, we report the structure-activity relationship (SAR) to develop novel mGlu negative allosteric modulator (NAM) scaffolds devoid of the aryl/heterobiaryl acetylene moiety found in many historic mGlu NAMs, which has been linked to metabolic liabilities and hepatotoxicity. This endeavor utilized a scaffold-hopping strategy from the predecessor compound , in which we replace an ether-linked tetrahydrofuran with various carbon-linked heteroaryl motifs to generate highly potent and selective mGlu NAMs. One such compound, , displayed low nanomolar potency against human mGlu and was highly brain penetrant. Moreover, showed a vast improvement in predicted human hepatic clearance versus predecessor compound .

Tags: 2026