Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.
Antiparkinson Agents
/ chemical synthesis
Biological Availability
Brain
/ metabolism
Drug Design
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/ antagonists & inhibitors
Models, Molecular
Protein Kinase Inhibitors
/ pharmacology
Quinazolines
/ chemical synthesis
Structure-Activity Relationship
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 01 2022
13 01 2022
Historique:
pubmed:
31
12
2021
medline:
8
2
2022
entrez:
30
12
2021
Statut:
ppublish
Résumé
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds
Identifiants
pubmed: 34967623
doi: 10.1021/acs.jmedchem.1c01968
doi:
Substances chimiques
Antiparkinson Agents
0
Protein Kinase Inhibitors
0
Quinazolines
0
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM