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

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
Bioorg Med Chem Lett. 2017 27 (23): 5179-5184

PMID: 29089231 · PMCID: PMC6542369 · DOI:10.1016/j.bmcl.2017.10.053

Herein we describe the continued optimization of M 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.

Copyright © 2017 Elsevier Ltd. All rights reserved.

MeSH Terms (9)

Allosteric Regulation Amides Azetidines Drug Evaluation, Preclinical Humans Protein Binding Pyridazines Receptor, Muscarinic M4 Structure-Activity Relationship

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