Evidence map›Paper›PMID 37583812›Full record

ArticleACS medicinal chemistry letters2023

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Michael T Rudd, Peter J Manley, Barbara Hanney, Zhaoyang Meng, Youheng Shu, Pablo de Leon, Jessica L Frie, Yongxin Han, Jenny Miu-Chun Wai, Zhi-Qiang Yang and 25 more

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

Article in ACS medicinal chemistry letters, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
1.0field-weighted citation impact, top 26% 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

6 citing papers in PubMed, 7 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Article
  6. Discovery of [ACS medicinal chemistry letters · 2023
    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

35 authors at 2 institutions in 1 country.

Michael T RuddDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.ORCID https://orcid.org/0000-0002-4033-0456
Peter J ManleyDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Barbara HanneyDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Zhaoyang MengDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Youheng ShuDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Pablo de LeonDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Jessica L FrieDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Yongxin HanExternal Discovery Chemistry, Merck & Co., Inc, Boston, Massachusetts 02115, United States.ORCID https://orcid.org/0000-0002-3014-035X
Jenny Miu-Chun WaiDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Zhi-Qiang YangDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
James J PerkinsDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.ORCID https://orcid.org/0000-0002-3243-5311
Danielle M HurzyDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Jesse J ManikowskiDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Hong ZhuDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Christopher J BungardDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.ORCID https://orcid.org/0000-0002-2523-5266
Antonella ConversoDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Robert S MeissnerDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Mali L CosdenDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Ikuo HayashiDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Lei MaDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Julie O'BrienDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Victor N UebeleDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Joel B SchachterDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Neetesh BhandariDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Gwendolyn J WardDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Kerry L FillgroveDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Bing LuDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Yuexia LiangDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
David C DubostDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Vanita PuriDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Donnie M EddinsDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Joshua D VardiganDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Robert E DroletDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Jonathan T KernDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.
Jason M UslanerDepartments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.ORCID https://orcid.org/0000-0002-8952-5940
United States Military Academy · USMerck & Co., Inc., Rahway, NJ, USA (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

Identifiers

PMID37583812
PMCPMC10424309
OpenAlexW4384070435

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.