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Bioorg Med Chem Lett. 2016 Jan 15;26(2):257-261. doi: 10.1016/j.bmcl.2015.12.052. Epub 2015 Dec 17.

Preclinical characterization of substituted 6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one P2X7 receptor antagonists.

Author information

1
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.

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

PMID:
26707399
DOI:
10.1016/j.bmcl.2015.12.052
[Indexed for MEDLINE]

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