Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists

Aaron M. Bender; Rebecca L. Weiner; Vincent B. Luscombe; Sonia Ajmera; Hyekyung P. Cho; Sichen Chang; Xiaoyan Zhan; Alice L. Rodriguez; Colleen M. Niswender; Darren W. Engers; Thomas M. Bridges; P. Jeffrey Conn; Craig W. Lindsley

doi:10.1016/j.bmcl.2017.05.042

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Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists

Journal article

Peer reviewed

Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists

Aaron M. Bender, Rebecca L. Weiner, Vincent B. Luscombe, Sonia Ajmera, Hyekyung P. Cho, Sichen Chang, Xiaoyan Zhan, Alice L. Rodriguez, Colleen M. Niswender, Darren W. Engers, …

Bioorganic & medicinal chemistry letters, Vol.27(15), pp.3576-3581

08/01/2017

DOI: 10.1016/j.bmcl.2017.05.042

PMCID: PMC6659418

PMID: 28633897

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https://www.ncbi.nlm.nih.gov/pmc/articles/6659418View

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Abstract

[Display omitted] This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp=2.1, Kp,uu=1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists.

DMPK

Muscarinic acetylcholine receptor

pan-Antagonist

Pyridazine

Structure-activity relationship (SAR)

Details

Title: Subtitle: Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists
Creators: Aaron M. Bender - Vanderbilt University
Rebecca L. Weiner - Vanderbilt University
Vincent B. Luscombe - Vanderbilt University
Sonia Ajmera - Vanderbilt University
Hyekyung P. Cho - Vanderbilt University
Sichen Chang - Vanderbilt University
Xiaoyan Zhan - Vanderbilt University
Alice L. Rodriguez - Vanderbilt University
Colleen M. Niswender - Vanderbilt University
Darren W. Engers - Vanderbilt University
Thomas M. Bridges - Vanderbilt University
P. Jeffrey Conn - Vanderbilt University
Craig W. Lindsley - Vanderbilt University
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry letters, Vol.27(15), pp.3576-3581
DOI: 10.1016/j.bmcl.2017.05.042
PMID: 28633897
PMCID: PMC6659418
NLM abbreviation: Bioorg Med Chem Lett
ISSN: 0960-894X
eISSN: 1464-3405
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100000002, name: NIH
Language: English
Date published: 08/01/2017
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984353888302771

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