2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors.
A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.
Cole
Andrew G
AG
Ligand Pharmaceuticals, Inc, Cranbury, NJ 08512, USA. acole@ligand.com
Bohnstedt
Adolph C
AC
Paradkar
Vidyadhar
V
Kingsbury
Celia
C
Quintero
Jorge G
JG
Park
Haengsoon
H
Lu
Yingchun
Y
You
Ming
M
Neagu
Irina
I
Diller
David J
DJ
Letourneau
Jeffrey J
JJ
Shao
Yuefei
Y
James
Ray A
RA
Riviello
Christopher M
CM
Ho
Koc-Kan
KK
Lin
Tsung H
TH
Wang
Bojing
B
Appell
Kenneth C
KC
Sills
Matthew
M
Quadros
Elizabeth
E
Kimble
Earl F
EF
Ohlmeyer
Michael H J
MH
Webb
Maria L
ML
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D051379:Mice; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011687:Purines; D007371:Interferon-gamma; D053616:Janus Kinase 3