Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
Department of Discovery Chemistry, Genentech, Inc, South San Francisco, CA 94080, USA. mzak@gene.com
Mark
M
Zak
Rohan
R
Mendonca
Mercedesz
M
Balazs
Kathy
K
Barrett
Philippe
P
Bergeron
Wade S
WS
Blair
Christine
C
Chang
Gauri
G
Deshmukh
Jason
J
Devoss
Peter S
PS
Dragovich
Charles
C
Eigenbrot
Nico
N
Ghilardi
Paul
P
Gibbons
Stefan
S
Gradl
Chris
C
Hamman
Emily J
EJ
Hanan
Eric
E
Harstad
Peter R
PR
Hewitt
Christopher A
CA
Hurley
Tian
T
Jin
Adam
A
Johnson
Tony
T
Johnson
Jane R
JR
Kenny
Michael F T
MF
Koehler
Pawan
P
Bir Kohli
Janusz J
JJ
Kulagowski
Sharada
S
Labadie
Jiangpeng
J
Liao
Marya
M
Liimatta
Zhonghua
Z
Lin
Patrick J
PJ
Lupardus
Robert J
RJ
Maxey
Jeremy M
JM
Murray
Rebecca
R
Pulk
Madeleine
M
Rodriguez
Scott
S
Savage
Steven
S
Shia
Micah
M
Steffek
Savita
S
Ubhayakar
Mark
M
Ultsch
Anne
A
van Abbema
Stuart I
SI
Ward
Ling
L
Xiao
Yisong
Y
Xiao
D000818:Animals; D001681:Biological Assay; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D022781:Hepatocytes / Q000166:cytology; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship
D006575:Heterocyclic Compounds, 3-Ring; D053613:Janus Kinase 1; D053614:Janus Kinase 2