Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.

Mice Animals Sirolimus MTOR Inhibitors Syndrome Central Nervous System / metabolism Brain / metabolism TOR Serine-Threonine Kinases Adenosine Triphosphate

Journal

Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531

Informations de publication

Date de publication:
13 07 2023
Historique:
medline: 14 7 2023
pubmed: 3 7 2023
entrez: 3 7 2023
Statut: ppublish

Résumé

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (

Identifiants

DOI: 10.1021/acs.jmedchem.3c00705 PMID: 37399505
pubmed: 37399505
doi: 10.1021/acs.jmedchem.3c00705
doi:

Substances chimiques

Sirolimus W36ZG6FT64
MTOR Inhibitors 0
TOR Serine-Threonine Kinases EC 2.7.11.1
Adenosine Triphosphate 8L70Q75FXE

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

9095-9119

Auteurs

Simone Bonazzi (S)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
ORCID: 0000-0001-5698-3155

Audrey Gray (A)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Noel M Thomsen (NM)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Jonathan Biag (J)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Nancy Labbe-Giguere (N)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Erin P Keaney (EP)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Hasnain A Malik (HA)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Yingchuan Sun (Y)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Jill Nunez (J)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Rajeshri G Karki (RG)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
ORCID: 0000-0003-2210-5789

Mark Knapp (M)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5959 Horton St, Emeryville, California 94608, United States.

Robert Elling (R)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5959 Horton St, Emeryville, California 94608, United States.

John Fuller (J)

Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 5959 Horton St, Emeryville, California 94608, United States.

Gwynn Pardee (G)

Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 5959 Horton St, Emeryville, California 94608, United States.

Lucas Craig (L)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Ketthsy Capre (K)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Sarah Salas (S)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Aakruti Gorde (A)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Guiqing Liang (G)

Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Danuta Lubicka (D)

Global Drug Development/Technical Research and Development, Novartis Institutes for BioMedical Research, 700 Main Street, Cambridge, Massachusetts 02139, United States.

Stephanie M McTighe (SM)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Carleton Goold (C)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Shanming Liu (S)

Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Lin Deng (L)

Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Jin Hong (J)

Preclinical Safety, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Alexander Fekete (A)

Preclinical Safety, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Pascal Stadelmann (P)

Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 28, 4056 Basel, Switzerland.

Wilfried Frieauff (W)

Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 28, 4056 Basel, Switzerland.

Azeddine Elhajouji (A)

Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 28, 4056 Basel, Switzerland.

Daniel Bauer (D)

Preclinical Safety, Novartis Institutes for BioMedical Research, Fabrikstrasse 28, 4056 Basel, Switzerland.
ORCID: 0000-0001-5751-2988

Andreas Lerchner (A)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabrikstrasse 22, 4056 Basel, Switzerland.

Branko Radetich (B)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Pascal Furet (P)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabrikstrasse 22, 4056 Basel, Switzerland.

Grazia Piizzi (G)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Doug Burdette (D)

Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Christopher J Wilson (CJ)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Stefan Peukert (S)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Lawrence G Hamann (LG)

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Leon O Murphy (LO)

Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 181 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.

Daniel Curtis (D)

Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Identification of Brain-Penetrant...
questionsmedicales.fr › Eucaryotes › Animaux › Identification of Brain-Penetrant...
questionsmedicales.fr › Composés chimiques organiques › Lactones › Sirolimus › Identification of Brain-Penetrant...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Inhibiteurs de mTOR › Identification of Brain-Penetrant...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Maladie › Syndrome › Identification of Brain-Penetrant...
questionsmedicales.fr › Système nerveux › Système nerveux central › Identification of Brain-Penetrant...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Identification of Brain-Penetrant...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Identification of Brain-Penetrant...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › Adénosine triphosphate › Identification of Brain-Penetrant...