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Identification of Amides as Carboxylic Acid Surrogates for Quinolizidinone-Based M1 Positive Allosteric Modulators

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† Departments of †Medicinal Chemistry, ‡Alzheimer's Research, and §Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States
*Tel: 215-652-5147. Fax: 215-652-3971. E-mail: [email protected]
Cite this: ACS Med. Chem. Lett. 2012, 3, 12, 1070–1074
Publication Date (Web):October 13, 2012
https://doi.org/10.1021/ml300280g
Copyright © 2012 American Chemical Society
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    Abstract

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    Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic receptor positive allosteric modulators, and leading pyran 4o and cyclohexane 5c were found to possess good potency and in vivo efficacy.

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    17. Bruce J. Melancon, Corey R. Hopkins. Muscarinic Receptors Allosteric Modulation. 2016, 175-193. https://doi.org/10.1039/9781782629276-00175
    18. Beatriz Fernandez, Mark R.J. Elsegood, Gary Fairley, Gareth J. Pritchard, Simon J. Teat, George W. Weaver. Isolation and structure determination of the first example of the azeto[2,3-c]quinolizinedione ring system. Tetrahedron Letters 2015, 56 (36) , 5120-5122. https://doi.org/10.1016/j.tetlet.2015.07.029
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