title: Preclinical characterization of substituted 6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one P2X7 receptor antagonists.
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).
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ameriks
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Suchitra
authors.initials: S
authors.lastname: Ravula
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Rech
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Brad M
authors.initials: BM
authors.lastname: Savall
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Wall
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D018938:Caco-2 Cells; D002491:Central Nervous System Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014316:Tritium
chemical_list: C000609564:7-(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; D002491:Central Nervous System Agents; D058920:Purinergic P2X Receptor Antagonists; D011719:Pyrazines; D058486:Receptors, Purinergic P2X7; D014230:Triazoles; D014316:Tritium
keywords: 6,7-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one; Autoradiography; CNS; Depression; P2X7