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5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Jan 15; Vol. 29 (2), pp. 212-215. Date of Electronic Publication: 2018 Nov 28. - Publication Year :
- 2019
-
Abstract
- We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Benzamides chemical synthesis
Benzamides chemistry
Brain metabolism
Dose-Response Relationship, Drug
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 metabolism
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Pyridazines chemical synthesis
Pyridazines chemistry
Structure-Activity Relationship
Benzamides pharmacology
Brain drug effects
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Pyridazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 29
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30522952
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.11.054