title: Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain.
abstract: Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC50 = 9 nM; rat P2X7 IC50 = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure-activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included.
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Christa C
authors.initials: CC
authors.lastname: Chrovian
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Akinola
authors.initials: A
authors.lastname: Soyode-Johnson
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Genesis M
authors.initials: GM
authors.lastname: Bacani
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Leslie
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Rech
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D011485:Protein Binding / Q000187:drug effects; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D011719:Pyrazines
keywords: P2X7; SAR; brain permeability; mood disorders; receptor occupancy