title: Substituted 5,6-(Dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-methanones as P2X7 Antagonists.
abstract: We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potency at both the rat and human P2X7 receptors. Disclosed herein are druglike molecules with demonstrated target engagement of the rat P2X7 receptors after an oral dose. Specifically, compound 20 occupied the P2X7 receptors >80% over the 6 h time course as measured by an ex vivo radioligand binding experiment. In a dose-response assay, this molecule has a plasma EC50 of 8 ng/mL. Overall, 20 has suitable druglike properties and pharmacokinetics in rat and dog. This molecule and others disclosed herein will serve as additional tools to elucidate the role of the P2X7 receptor in neuropsychiatric disorders.
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Ziff
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Dale A
authors.initials: DA
authors.lastname: Rudolph
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Brice
authors.initials: B
authors.lastname: Stenne
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Koudriakova
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.affiliation: Janssen Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Brock T
authors.initials: BT
authors.lastname: Shireman
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*
chemical_list: C539459:2-cyano-1-((1S)-1-phenylethyl)-3-quinolin-5-ylguanidine; D016207:Cytokines; D004151:Dipeptides; D006146:Guanidines; D058920:Purinergic P2X Receptor Antagonists; D011804:Quinolines; D058486:Receptors, Purinergic P2X7; C028342:compound 20
keywords: 5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl) methanones; CNS; IL-1β; P2X7; depression; neuroinflammation