Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides

Bioorganic & Medicinal Chemistry Letters
James C TarrCraig W Lindsley

Abstract

Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.

Citations

Jun 16, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Baptiste BarréJanine Cossy
Jun 30, 2021·Archiv der Pharmazie·Deepa R ParmarAnand G Vala
Jul 28, 2021·The Journal of Organic Chemistry·Xiaoshen Ma, Charles S Yeung
Aug 15, 2018·Journal of Medicinal Chemistry·Eric A WoldJia Zhou

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