• Bioorg. Med. Chem. Lett. · Aug 2016

    Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.

    • Joseph D Panarese, Hykeyung P Cho, Jeffrey J Adams, Kellie D Nance, Pedro M Garcia-Barrantes, Sichen Chang, Ryan D Morrison, Anna L Blobaum, Colleen M Niswender, Shaun R Stauffer, P Jeffrey Conn, and Craig W Lindsley.
    • Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
    • Bioorg. Med. Chem. Lett. 2016 Aug 1; 26 (15): 3822-5.

    AbstractThis Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.Copyright © 2016 Elsevier Ltd. All rights reserved.

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