title: Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2.
abstract: Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.
authors.affiliation: Small Molecule Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. sharadal@gene.com
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Kathy
authors.initials: K
authors.lastname: Barrett
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Philippe
authors.initials: P
authors.lastname: Bergeron
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hurley
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.forename: Pawan Bir
authors.initials: PB
authors.lastname: Kohli
authors.forename: Janusz J
authors.initials: JJ
authors.lastname: Kulagowski
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lupardus
authors.forename: Rohan
authors.initials: R
authors.lastname: Mendonca
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Murray
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pulk
authors.forename: Steven
authors.initials: S
authors.lastname: Shia
authors.forename: Micah
authors.initials: M
authors.lastname: Steffek
authors.forename: Savita
authors.initials: S
authors.lastname: Ubhayakar
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Anne
authors.initials: A
authors.lastname: van Abbema
authors.forename: Stuart
authors.initials: S
authors.lastname: Ward
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D053613:Janus Kinase 1; D053614:Janus Kinase 2