The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead.
This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.
Department of Chemistry, Merck & Co., Boston, MA 02115, USA. tony_siu@merck.com
Tony
T
Siu
Ekaterina S
ES
Kozina
Joon
J
Jung
Craig
C
Rosenstein
Anjili
A
Mathur
Michael D
MD
Altman
Grace
G
Chan
Lin
L
Xu
Eric
E
Bachman
Jan-Rung
JR
Mo
Melaney
M
Bouthillette
Thomas
T
Rush
Christopher J
CJ
Dinsmore
C Gary
CG
Marshall
Jonathan R
JR
Young
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D003500:Cyclization; D004353:Drug Evaluation, Preclinical; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship
D006575:Heterocyclic Compounds, 3-Ring; D011728:Pyridones; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2