Abstract
The synthesis, SAR, and preclinical characterization of a series of substituted 6,7-dihydro[1,2,4]triazolo[4,3]pyrazin-8(5H)-one P2X7 receptor antagonists are described. Optimized leads from this series comprise some of the most potent human P2X7R antagonists reported to date (IC50s<1nM). They also exhibit sufficient potency and oral bioavailability in rat to enable extensive in vivo profiling. Although many of the disclosed compounds are peripherally restricted, compound 11d is brain penetrant and upon oral administration demonstrated dose-dependent target engagement in rat hippocampus as determined by ex vivo receptor occupancy with radiotracer 5 (ED50=0.8mg/kg).
Keywords:
6,7-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one; Autoradiography; CNS; Depression; P2X7.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
-
Animals
-
Blood-Brain Barrier / metabolism
-
Caco-2 Cells
-
Central Nervous System Agents / chemical synthesis
-
Central Nervous System Agents / pharmacokinetics
-
Central Nervous System Agents / pharmacology*
-
Hippocampus / metabolism
-
Humans
-
Microsomes, Liver / metabolism
-
Purinergic P2X Receptor Antagonists / chemical synthesis
-
Purinergic P2X Receptor Antagonists / pharmacokinetics
-
Purinergic P2X Receptor Antagonists / pharmacology*
-
Pyrazines / chemical synthesis
-
Pyrazines / pharmacokinetics
-
Pyrazines / pharmacology*
-
Rats
-
Receptors, Purinergic P2X7 / metabolism
-
Stereoisomerism
-
Structure-Activity Relationship
-
Triazoles / chemical synthesis
-
Triazoles / pharmacokinetics
-
Triazoles / pharmacology*
-
Tritium
Substances
-
7-(2-chloro-3-(trifluoromethyl)benzyl)-6-methyl-3-pyrimidin-2-yl-6,7-dihydro(1,2,4)triazolo(4,3-a)pyrazin-8(5H)-one
-
Central Nervous System Agents
-
Purinergic P2X Receptor Antagonists
-
Pyrazines
-
Receptors, Purinergic P2X7
-
Triazoles
-
Tritium