title: Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2.
abstract: Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
authors: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. mzak@gene.com
authors: Mark
authors: M
authors: Zak
authors: Christopher A
authors: CA
authors: Hurley
authors: Stuart I
authors: SI
authors: Ward
authors: Philippe
authors: P
authors: Bergeron
authors: Kathy
authors: K
authors: Barrett
authors: Mercedesz
authors: M
authors: Balazs
authors: Wade S
authors: WS
authors: Blair
authors: Richard
authors: R
authors: Bull
authors: Paroma
authors: P
authors: Chakravarty
authors: Christine
authors: C
authors: Chang
authors: Peter
authors: P
authors: Crackett
authors: Gauri
authors: G
authors: Deshmukh
authors: Jason
authors: J
authors: DeVoss
authors: Peter S
authors: PS
authors: Dragovich
authors: Charles
authors: C
authors: Eigenbrot
authors: Charles
authors: C
authors: Ellwood
authors: Simon
authors: S
authors: Gaines
authors: Nico
authors: N
authors: Ghilardi
authors: Paul
authors: P
authors: Gibbons
authors: Stefan
authors: S
authors: Gradl
authors: Peter
authors: P
authors: Gribling
authors: Chris
authors: C
authors: Hamman
authors: Eric
authors: E
authors: Harstad
authors: Peter
authors: P
authors: Hewitt
authors: Adam
authors: A
authors: Johnson
authors: Tony
authors: T
authors: Johnson
authors: Jane R
authors: JR
authors: Kenny
authors: Michael F T
authors: MF
authors: Koehler
authors: Pawan
authors: P
authors: Bir Kohli
authors: Sharada
authors: S
authors: Labadie
authors: Wyne P
authors: WP
authors: Lee
authors: Jiangpeng
authors: J
authors: Liao
authors: Marya
authors: M
authors: Liimatta
authors: Rohan
authors: R
authors: Mendonca
authors: Raman
authors: R
authors: Narukulla
authors: Rebecca
authors: R
authors: Pulk
authors: Austin
authors: A
authors: Reeve
authors: Scott
authors: S
authors: Savage
authors: Steven
authors: S
authors: Shia
authors: Micah
authors: M
authors: Steffek
authors: Savita
authors: S
authors: Ubhayakar
authors: Anne
authors: A
authors: van Abbema
authors: Ignacio
authors: I
authors: Aliagas
authors: Barbara
authors: B
authors: Avitabile-Woo
authors: Yisong
authors: Y
authors: Xiao
authors: Jing
authors: J
authors: Yang
authors: Janusz J
authors: JJ
authors: Kulagowski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000209:etiology; D001682:Biological Availability; D002463:Cell Membrane Permeability; D003094:Collagen; D018360:Crystallography, X-Ray; D004285:Dogs; D000882:Haplorhini; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D061985:Madin Darby Canine Kidney Cells; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
chemical_list: C582929:4-(2-(1-hydroxyethyl)imidazo(4,5-d)pyrrolo(2,3-b)pyridin-1(6H)-yl)cyclohexanecarbonitrile; D018501:Antirheumatic Agents; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D011758:Pyrroles; D003094:Collagen; D053613:Janus Kinase 1; D053614:Janus Kinase 2