title: Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists.
abstract: The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 =7 .7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Dale A
authors.initials: DA
authors.lastname: Rudolph
authors.affiliation: Janssen Research & Development, Discovery Sciences, A Division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Alcazar
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 Research & Development, Discovery Sciences, A Division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Anton
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: Pascal
authors.initials: P
authors.lastname: Bonaventure
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: Christa C
authors.initials: CC
authors.lastname: Chrovian
authors.affiliation: Janssen Research & Development, Discovery Sciences, A Division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain.
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
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: 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: 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 Research & Development, Discovery Sciences, A Division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain.
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Andres
authors.affiliation: Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: mletavic@its.jnj.com.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
mesh_terms: D000818:Animals; D006207:Half-Life; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D011485:Protein Binding; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011719:Pyrazines / Q000737:chemistry*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D011719:Pyrazines; D058486:Receptors, Purinergic P2X7; D014230:Triazoles
keywords: 5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones; CNS; Depression; P2X7