title: Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors.
abstract: Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA. Electronic address: michael.friedman@abbvie.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedman
authors.affiliation: Abbvie, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Frank
authors.affiliation: Abbvie, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Argiriadi
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Davis
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: George
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: George
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Goedken
authors.affiliation: Materia Inc, 60 N San Gabriel Blvd., Pasadena, CA 91107, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Fiamengo
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hyland
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis, Pasteur Boston, MA 02115, USA.
authors.forename: Anwar
authors.initials: A
authors.lastname: Murtaza
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morytko
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Gagandeep
authors.initials: G
authors.lastname: Somal
authors.affiliation: Abbvie, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Stewart
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Edit
authors.initials: E
authors.lastname: Tarcsa
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Van Epps
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Voss
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Abbvie, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Woller
authors.affiliation: Abbvie Bioresearch Center, 381 Plantation St., Worcester, MA 01605, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Wishart
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000606689:6H-pyrrolo(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D014230:Triazoles; C507904:JAK1 protein, human; D053613:Janus Kinase 1
keywords: 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines; Jak inhibitors; Jak selectivity; Tricyclic pyrrolopyrazines