Pyrazolone based TGFbetaR1 kinase inhibitors.
Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.
Guckian
Kevin
K
Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. kevin.guckian@biogenidec.com
Carter
Mary Beth
MB
Lin
Edward Yin-Shiang
EY
Choi
Michael
M
Sun
Lihong
L
Boriack-Sjodin
P Ann
PA
Chuaqui
Claudio
C
Lane
Benjamin
B
Cheung
Kam
K
Ling
Leona
L
Lee
Wen-Cherng
WC
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047069:Pyrazolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D047069:Pyrazolones; D018125:Receptors, Transforming Growth Factor beta; C038362:pyrazolone; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat