title: Pyrazolone based TGFbetaR1 kinase inhibitors.
abstract: 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.
authors.affiliation: Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. kevin.guckian@biogenidec.com
authors.forename: Kevin
authors.initials: K
authors.lastname: Guckian
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Carter
authors.forename: Edward Yin-Shiang
authors.initials: EY
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Choi
authors.forename: Lihong
authors.initials: L
authors.lastname: Sun
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lane
authors.forename: Kam
authors.initials: K
authors.lastname: Cheung
authors.forename: Leona
authors.initials: L
authors.lastname: Ling
authors.forename: Wen-Cherng
authors.initials: WC
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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