Discovery of 7-(Pyridin-3-yl)thieno[3,2- <i>b</i> ]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 <b>VU6031545</b>, 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, <b>VU6035386</b>, displayed low nanomolar potency against human mGlu₅ and was highly brain penetrant. Moreover, <b>VU6035386</b> showed a vast improvement in predicted human hepatic clearance versus predecessor compound <b>VU6031545</b>.