Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core

Blake R. Bewley; Paul K. Spearing; Rebecca L. Weiner; Vincent B. Luscombe; Xiaoyan Zhan; Sichen Chang; Hyekyung P. Cho; Alice L. Rodriguez; Colleen M. Niswender; P. Jeffrey Conn; Thomas M. Bridges; Darren W. Engers; Craig W. Lindsley

doi:10.1016/j.bmcl.2017.08.043

Back

Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core

Journal article

Peer reviewed

Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core

Blake R. Bewley, Paul K. Spearing, Rebecca L. Weiner, Vincent B. Luscombe, Xiaoyan Zhan, Sichen Chang, Hyekyung P. Cho, Alice L. Rodriguez, Colleen M. Niswender, P. Jeffrey Conn, …

Bioorganic & medicinal chemistry letters, Vol.27(18), pp.4274-4279

09/15/2017

DOI: 10.1016/j.bmcl.2017.08.043

PMCID: PMC5688877

PMID: 28866269

View Online

Abstract

[Display omitted] This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp=5.3, Kp,uu=2.4; MDCK-MDR1 (P-gp) ER=1.1).

Muscarinic acetylcholine receptor

Non-human primate (NHP)

Positive allosteric modulator (PAM)

Structure-activity relationship (SAR)

Details

Title: Subtitle: Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core
Creators: Blake R. Bewley - Vanderbilt University
Paul K. Spearing - Vanderbilt University
Rebecca L. Weiner - Vanderbilt University
Vincent B. Luscombe - Vanderbilt University
Xiaoyan Zhan - Vanderbilt University
Sichen Chang - Vanderbilt University
Hyekyung P. Cho - Vanderbilt University
Alice L. Rodriguez - Vanderbilt University
Colleen M. Niswender - Vanderbilt University
P. Jeffrey Conn - Vanderbilt University
Thomas M. Bridges - Vanderbilt University
Darren W. Engers - Vanderbilt University
Craig W. Lindsley - Vanderbilt University
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry letters, Vol.27(18), pp.4274-4279
DOI: 10.1016/j.bmcl.2017.08.043
PMID: 28866269
PMCID: PMC5688877
NLM abbreviation: Bioorg Med Chem Lett
ISSN: 0960-894X
eISSN: 1464-3405
Publisher: Elsevier Ltd
Language: English
Date published: 09/15/2017
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984353826902771

Metrics

11 Record Views

11 Times Cited - Web of Science

See more details