Discovery of a potent M5 antagonist with improved clearance profile. Part 2: Pyrrolidine amide-based antagonists

This Letter describes our ongoing effort to improve the clearance of selective M5 antagonists. Herein, we report the replacement of the previously disclosed piperidine amide (4, disclosed in Part 1) with a pyrrolidine amide core. Several compounds within this series provided good potency, subtype selectivity, and low to moderate clearance profiles. Interestingly, the left-hand side SAR for this series diverged from our earlier efforts.

Automated summary

This Letter describes the ongoing effort to improve the clearance of selective M5 antagonists, reporting the replacement of the previously disclosed piperidine amide with a pyrrolidine amide core. The compounds in this series showed good potency, subtype selectivity, and moderate to low clearance profiles. Interestingly, the SAR for this series diverged from previous efforts.