Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2

This Letter details our efforts to develop novel tricyclic M-4 PAM scaffolds with improved pharmacological properties. This endeavor involved a tie-back strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyri-dine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3 ',2 ':4,5] thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c ']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M-4 receptor.

Automated summary

The Letter details efforts to develop novel tricyclic M-4 PAM scaffolds with improved pharmacological properties. A tie-back strategy was employed to replace the core structure, leading to the discovery of two novel tricyclic cores with low nanomolar potency against the human M-4 receptor.