4区 · 医学
Article
作者: Daniels, J Scott ; Emmitte, Kyle A ; Morrison, Ryan D ; Niswender, Colleen M ; Rodriguez, Alice L ; Lindsley, Craig W ; Venable, Daryl F ; Jones, Carrie K ; Byers, Frank W ; Bates, Brittney S ; Lawson, Kera P ; Conn, P Jeffrey ; Blobaum, Anna L ; Felts, Andrew S
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects.