Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M-4 positive allosteric modulator (PAM) chemotype via scaffold hopping

Madeline F. Long; Julie L. Engers; Sichen Chang; Xiaoyan Zhan; Rebecca L. Weiner; Vincent B. Luscombe; Alice L. Rodriguez; Hyekyung P. Cho; Colleen M. Niswender; Thomas M. Bridges; P. Jeffrey Conn; Darren W. Engers; Craig W. Lindsley

doi:10.1016/j.bmcl.2017.10.016

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Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M-4 positive allosteric modulator (PAM) chemotype via scaffold hopping

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Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M-4 positive allosteric modulator (PAM) chemotype via scaffold hopping

Madeline F. Long, Julie L. Engers, Sichen Chang, Xiaoyan Zhan, Rebecca L. Weiner, Vincent B. Luscombe, Alice L. Rodriguez, Hyekyung P. Cho, Colleen M. Niswender, Thomas M. Bridges, …

Bioorganic & medicinal chemistry letters, Vol.27(22), pp.4999-5001

11/15/2017

DOI: 10.1016/j.bmcl.2017.10.016

PMCID: PMC5784840

PMID: 29037946

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https://www.ncbi.nlm.nih.gov/pmc/articles/5784840View

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Abstract

This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M-4 PAM activity in most M-4 PAMs to date, within the thieno[2,3-b]pyridine core, as the beta-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M-4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core. (C) 2017 Elsevier Ltd. All rights reserved.

Chemistry

Chemistry, Medicinal

Chemistry, Organic

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Physical Sciences

Science & Technology

Details

Title: Subtitle: Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M-4 positive allosteric modulator (PAM) chemotype via scaffold hopping
Creators: Madeline F. Long - Vanderbilt University
Julie L. Engers - Vanderbilt University
Sichen Chang - Vanderbilt University
Xiaoyan Zhan - Vanderbilt University
Rebecca L. Weiner - Vanderbilt University
Vincent B. Luscombe - Vanderbilt University
Alice L. Rodriguez - Vanderbilt University
Hyekyung P. Cho - Vanderbilt University
Colleen M. Niswender - Vanderbilt University
Thomas M. Bridges - Vanderbilt University
P. Jeffrey Conn - Vanderbilt University
Darren W. Engers - Vanderbilt University
Craig W. Lindsley - Vanderbilt University
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry letters, Vol.27(22), pp.4999-5001
DOI: 10.1016/j.bmcl.2017.10.016
PMID: 29037946
PMCID: PMC5784840
NLM abbreviation: Bioorg Med Chem Lett
ISSN: 0960-894X
eISSN: 1464-3405
Publisher: Elsevier
Number of pages: 3
Grant note: William K. Warren Foundation 1X01 MH077607 / NIH via the NIH Roadmap Initiative U01MH087965 / Vanderbilt NCDDG U54HD083211 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) U54MH084659 / Molecular Libraries Probe Center Network U54MH084659 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
Language: English
Date published: 11/15/2017
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984353827302771

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