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

Herein, we report the structure–activity relationship (SAR) to develop novel mGlu5 negative allosteric modulator (NAM) scaffolds devoid of the aryl/heterobiaryl acetylene moiety found in many historic mGlu5 NAMs, which has been linked to metabolic liabilities and hepatotoxicity. This endeavor utilized a scaffold-hopping strategy from the predecessor compound VU6031545, in which we replace an ether-linked tetrahydrofuran with various carbon-linked heteroaryl motifs to generate highly potent and selective mGlu5 NAMs. One such compound, VU6035386, displayed low nanomolar potency against human mGlu5 and was highly brain penetrant. Moreover, VU6035386 showed a vast improvement in predicted human hepatic clearance versus predecessor compound VU6031545.