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Discovery of VU6008677: A Structurally Distinct Tricyclic M Positive Allosteric Modulator with Improved CYP450 Profile

Authors

Capstick RA Rory A , Bollinger SR Sean R , Engers JL Julie L , Long MF Madeline F , Chang S Sichen , Luscombe VB Vincent B , Rodriguez AL Alice L , Niswender CM Colleen M , Bridges TM Thomas M , Boutaud O Olivier , Conn PJ P Jeffrey , Engers DW Darren W , Lindsley CW Craig W , Temple KJ Kayla J .
ACS medicinal chemistry letters. 2024 07 03; 15(8).
1358-1366

Abstract

This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a “tie-back” strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3-]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3′,2′:4,5]thieno[3,2-]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3′,2′:4,5]furo[3,2-]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M and greatly reduced cytochrome P450 inhibition when compared with parent compound .