Evidence map›Paper›PMID 33007551›Full record

ArticleBioorganic & medicinal chemistry2020

Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators.

Kevin D Rynearson, Ronald N Buckle, R Jason Herr, Nicholas J Mayhew, Xinchao Chen, William D Paquette, Samuel A Sakwa, Jinhai Yang, Keith D Barnes, Phuong Nguyen and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
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

5 citing papers in PubMed.

  1. Article
  2. Review
  3. Review
  4. Article
  5. 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

15 authors.

Kevin D RynearsonDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, United States. Electronic address: krynearson@ucsd.edu.
Ronald N BuckleDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
R Jason HerrDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
Nicholas J MayhewDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
Xinchao ChenDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
William D PaquetteDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
Samuel A SakwaDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
Jinhai YangDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
Keith D BarnesDepartment of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
Phuong NguyenDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, United States.
William C MobleyDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, United States.
Graham JohnsonNuPharmAdvise, 3 Lakeside Drive, Sanbornton, NH 03269, United States.
Juinn H LinBiopharm Consulting Partners, 2 Willet Drive, Ambler, PA 19002, United States.
Rudolph E TanziGenetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, United States.
Steven L WagnerDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, United States; Veterans Administrative San Diego Healthcare System, La Jolla, CA 92161, United States. Electronic address: slwagner@health.ucsd.edu.

Funding

Optimization of Soluble Gamma-secretase Modulators for the Treatment of AlzheimerU01NS074501 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WAGNER, STEVEN LEE · 2011 to 2015
$1.4M
NINDS NIH HHS U01 NS074501
6 · The paper itself

Abstract

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aβ42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aβ42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aβ42 levels in the plasma of J20 mice, in addition to reducing Aβ42 levels in the plasma and brain of Tg2576 mice.

Indexed as

Drug DesignAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesAnimalsCell Line, TumorDose-Response Relationship, DrugEnzyme InhibitorsFemaleHumansMaleMiceMice, TransgenicMolecular StructurePyridinesStructure-Activity RelationshipAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesEnzyme InhibitorsPyridinesAlzheimer’s diseaseAmyloid betaAβ42 reductionGamma secretase modulatorMethoxypyridinesStructure activity relationship

Identifiers

PMID33007551
PMCPMC7917164

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

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.