title: Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists.
abstract: We describe the synthesis and SAR of 1,2,3-triazolopiperidines as a novel series of potent, brain penetrant P2X7 antagonists. Initial efforts yielded a series of potent human P2X7R antagonists with moderate to weak rodent potency, some CYP inhibition, poor metabolic stability, and low solubility. Further work in this series, which focused on the SAR of the N-linked heterocycle, not only increased the potency at the human P2X7R but also provided compounds with good potency at the rat P2X7R. These efforts eventually delivered a potent rat and human P2X7R antagonist with good physicochemical properties, an excellent pharmacokinetic profile, good partitioning into the CNS, and demonstrated in vivo target engagement after oral dosing.
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Brad M
authors.initials: BM
authors.lastname: Savall
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Duncan
authors.initials: D
authors.lastname: Wu
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 Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, 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, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
keywords: P2X7; depression; neuro-inflammation