Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype

Aaron M. Bender; Rebecca L. Weiner; Vincent B. Luscombe; Hyekyung P. Cho; Colleen M. Niswender; Darren W. Engers; Thomas M. Bridges; P. Jeffrey Conn; Craig W. Lindsley

doi:10.1016/j.bmcl.2017.04.009

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Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype

Journal article

Peer reviewed

Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype

Aaron M. Bender, Rebecca L. Weiner, Vincent B. Luscombe, Hyekyung P. Cho, Colleen M. Niswender, Darren W. Engers, Thomas M. Bridges, P. Jeffrey Conn and Craig W. Lindsley

Bioorganic & medicinal chemistry letters, Vol.27(11), pp.2479-2483

06/01/2017

DOI: 10.1016/j.bmcl.2017.04.009

PMCID: PMC5508519

PMID: 28427812

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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 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp=5.37mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M1–5, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.

DMPK

Muscarinic acetylcholine receptor

pan-Antagonist

Pyrimidine

Structure-activity relationship (SAR)

Details

Title: Subtitle: Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype
Creators: Aaron M. Bender - Vanderbilt University
Rebecca L. Weiner - Vanderbilt University
Vincent B. Luscombe - Vanderbilt University
Hyekyung P. Cho - 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(11), pp.2479-2483
DOI: 10.1016/j.bmcl.2017.04.009
PMID: 28427812
PMCID: PMC5508519
NLM abbreviation: Bioorg Med Chem Lett
ISSN: 0960-894X
eISSN: 1464-3405
Publisher: Elsevier Ltd
Language: English
Date published: 06/01/2017
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984353941202771

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