title: Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor.
abstract: The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED50 = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Devin M
authors.initials: DM
authors.lastname: Swanson
authors.affiliation: Janssen Pharmaceutical 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 Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Coe
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Freddy
authors.initials: F
authors.lastname: Schoetens
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Koudriakova
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Judith
authors.initials: J
authors.lastname: Skaptason
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wall
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Rech
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Xiahou
authors.initials: X
authors.lastname: Deng
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, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Anita
authors.initials: A
authors.lastname: Everson
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Scott
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Kia
authors.initials: K
authors.lastname: Sepassi
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.affiliation: Janssen Pharmaceutical 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 Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D054879:Halogenation; D000882:Haplorhini; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7