Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived...
Basic Information
ID: ALA4177638
Journal: Bioorg Med Chem Lett
Title: Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides.
Authors: Tarr JC, Wood MR, Noetzel MJ, Melancon BJ, Lamsal A, Luscombe VB, Rodriguez AL, Byers FW, Chang S, Cho HP, Engers DW, Jones CK, Niswender CM, Wood MW, Brandon NJ, Duggan ME, Conn PJ, Bridges TM, Lindsley CW.
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.
CiteXplore: 29089231
DOI: 10.1016/j.bmcl.2017.10.053
Patent ID: ┄