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Discovery of Thieno[3,2-]pyridine-5-carboxamide and 2,3-Difluorobenzamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Authors

Crocker KE Katherine E , Henderson SH Scott H , Capstick RA Rory A , Whomble DL David L , Bender AM Aaron M , Felts AS Andrew S , Han C Changho , Engers JL Julie L , Billard NB Natasha B , Maurer MA Mallory A , Cho HP Hyekyung P , Rodriguez AL Alice L , Niswender CM Colleen M , O'Neill J Jordan , Watson KJ Katherine J , Chang S Sichen , Blobaum AL Anna L , Boutaud O Olivier , Peng W Weimin , Rook JM Jerri M , Conn PJ P Jeffrey , Lindsley CW Craig W , Temple KJ Kayla J .
ACS medicinal chemistry letters. 2025 04 22; 16(5).
865-874

Abstract

This Letter describes the discovery of novel mGlu NAMs and . Starting from previously reported picolinamide compounds, a structure-activity relationship study of various core isosteres was conducted, leading to the identification of thieno[3,2-]pyridine-5-carboxamide and 2,3-difluorobenzamide as competent core replacements. These compounds are highly potent as well as brain penetrant with an IVIVC agreement and improved oral bioavailability in rats.