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

ABSTRACT: 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.

SUBMITTER: Orsi DL

PROVIDER: S-EPMC10938303 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Orsi Douglas L DL Felts Andrew S AS Rodriguez Alice L AL Vinson Paige N PN Cho Hyekyung P HP Chang Sichen S Blobaum Anna L AL Niswender Colleen M CM Conn P Jeffrey PJ Jones Carrie K CK Lindsley Craig W CW Han Changho C

Bioorganic & medicinal chemistry letters 20221010

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. ...[more]

PMID: 36228968

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