• Bioorg. Med. Chem. Lett. · Jul 2017

    Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.

    • James C Tarr, Michael R Wood, Meredith J Noetzel, Jeanette L Bertron, Rebecca L Weiner, Alice L Rodriguez, Atin Lamsal, Frank W Byers, Sichen Chang, Hyekyung P Cho, Carrie K Jones, Colleen M Niswender, Michael W Wood, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, and Craig W Lindsley.
    • Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
    • Bioorg. Med. Chem. Lett. 2017 Jul 1; 27 (13): 2990-2995.

    AbstractThis letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.Copyright © 2017 Elsevier Ltd. All rights reserved.

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