Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

James C Tarr; Michael R Wood; Meredith J Noetzel; Jeanette L Bertron; Rebecca L Weiner; Alice L Rodriguez; Atin Lamsal; Frank W Byers; Sichen Chang; Hyekyung P Cho; Carrie K Jones; Colleen M Niswender; Michael W Wood; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley

doi:10.1016/j.bmcl.2017.05.014

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Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

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Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

James C Tarr, Michael R Wood, Meredith J Noetzel, Jeanette L Bertron, Rebecca L Weiner, Alice L Rodriguez, Atin Lamsal, Frank W Byers, Sichen Chang, Hyekyung P Cho, …

Bioorganic & medicinal chemistry letters, Vol.27(13), pp.2990-2995

07/01/2017

DOI: 10.1016/j.bmcl.2017.05.014

PMCID: PMC5518475

PMID: 28522253

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https://doi.org/10.7270/q2ms3w6qView

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Abstract

This letter details the continued chemical optimization of a novel series of M positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.

Allosteric Regulation - drug effects

Amides - chemical synthesis

Amides - chemistry

Amides - pharmacology

Animals

Azetidines - chemical synthesis

Azetidines - chemistry

Azetidines - pharmacology

Disease Models, Animal

Dose-Response Relationship, Drug

Humans

Molecular Structure

Rats

Receptor, Muscarinic M4 - antagonists & inhibitors

Structure-Activity Relationship

Details

Title: Subtitle: Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides
Creators: James C Tarr - Vanderbilt University
Michael R Wood - Vanderbilt University
Meredith J Noetzel - Vanderbilt University
Jeanette L Bertron - Vanderbilt University
Rebecca L Weiner - Vanderbilt University
Alice L Rodriguez - Vanderbilt University
Atin Lamsal - Vanderbilt University
Frank W Byers - Vanderbilt University
Sichen Chang - Vanderbilt University
Hyekyung P Cho - Vanderbilt University
Carrie K Jones - Vanderbilt University
Colleen M Niswender - Vanderbilt University
Michael W Wood - Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
Nicholas J Brandon - Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
Mark E Duggan - Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
P Jeffrey Conn - Vanderbilt University
Thomas M Bridges - Vanderbilt University
Craig W Lindsley - Vanderbilt University
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry letters, Vol.27(13), pp.2990-2995
DOI: 10.1016/j.bmcl.2017.05.014
PMID: 28522253
PMCID: PMC5518475
NLM abbreviation: Bioorg Med Chem Lett
ISSN: 0960-894X
eISSN: 1464-3405
Grant note: U01 MH087965 / NIMH NIH HHS R01 MH073676 / NIMH NIH HHS U54 HD083211 / NICHD NIH HHS
Language: English
Date published: 07/01/2017
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984354057602771

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