Evidence map›Paper›PMID 27476142›Full record

ArticleBioorganic & medicinal chemistry letters2016

Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.

Michael R Wood, Meredith J Noetzel, James C Tarr, Alice L Rodriguez, Atin Lamsal, Sichen Chang, Jarrett J Foster, Emery Smith, Peter Chase, Peter S Hodder and 8 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
1.6field-weighted citation impact, top 16% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 12 citations in OpenAlex.

  1. Review
  2. Article
  3. Novel MBioorganic & medicinal chemistry letters · 2019
    Article
  4. Challenges in the development of an MBioorganic & medicinal chemistry letters · 2017
    Article
  5. Challenges in the development of an MBioorganic & medicinal chemistry letters · 2017
    Article
  6. Optimization of MBioorganic & medicinal chemistry letters · 2017
    Article
  7. Challenges in the development of an MBioorganic & medicinal chemistry letters · 2017
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 4 institutions in 1 country.

Michael R WoodVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Meredith J NoetzelVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
James C TarrVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Alice L RodriguezVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Atin LamsalVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Sichen ChangVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Jarrett J FosterVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Emery SmithThe Scripps Research Institutes Molecular Screening Center, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
Peter ChaseThe Scripps Research Institutes Molecular Screening Center, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
Peter S HodderAmgen Inc., Thousand Oaks, CA 91320, USA.
Darren W EngersVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Colleen M NiswenderVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Nicholas J BrandonNeuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
Michael W WoodNeuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
Mark E DugganNeuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
P Jeffrey ConnVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Thomas M BridgesVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: thomas.m.bridges@vanderbilt.edu.
Craig W LindsleyVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
Vanderbilt University · USAstraZeneca (United States) · USScripps Research Institute · USAmgen (United States) · US

Funding

UHTS Implementation(Florida)U54MH084512 · NIMH · SCRIPPS RESEARCH INSTITUTE, THE · PI ROSEN, HUGH · 2008 to 2013
$89.2M
The Vanderbilt Specialized Chemistry Center for Accelerated Probe DevelopmentU54MH084659 · NIMH · VANDERBILT UNIVERSITY · PI MEILER, JENS · 2008 to 2013
$24.1M
Muscarinic receptor activators as novel antipsychotic agentsR01MH073676 · NIMH · VANDERBILT UNIVERSITY · PI Jerri Michelle Rook · 2006 to 2026
$9.3M
Research Project: Sensory and Multisensory Contributions to AutismU54HD083211 · NICHD · VANDERBILT UNIVERSITY MEDICAL CENTER · PI DYKENS, ELISABETH MAY · 2015 to 2019
$7.1M
NICHD NIH HHS U54 HD083211NIMH NIH HHS R01 MH073676NIMH NIH HHS U54 MH084512NIMH NIH HHS U54 MH084659NIMH NIH HHS X01 MH077603
6 · The paper itself

Abstract

This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.

Indexed as

Drug DiscoveryAllosteric RegulationAnimalsCentral Nervous SystemHumansKetonesMolecular StructureReceptor, Muscarinic M1Structure-Activity RelationshipKetonesReceptor, Muscarinic M1M(4)Muscarinic acetylcholine receptorPositive allosteric modulator (PAM)SchizophreniaStructure–Activity Relationship (SAR)

Identifiers

PMID27476142
PMCPMC4987221
OpenAlexW2494601158

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.