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Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides

Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides

James C Tarr, Michael R Wood, Meredith J Noetzel, Bruce J Melancon, Atin Lamsal, Vincent B Luscombe, Alice L Rodriguez, Frank W Byers, Sichen Chang, Hyekyung P Cho, Darren W Engers, Carrie K Jones, Colleen M Niswender, etc.

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5179-5184.

PMID: 29089231

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP14075537	Potassium tetrafluoroborate		14075-53-7	Price

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