Rapid generation of a high quality lead for transforming growth factor-beta (TGF-beta) type I receptor (ALK5).
A novel class of 4-pyridinoxy-2-anilinopyridine-based TGF-beta type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors is reported. The binding mode of this scaffold was successfully predicted by analyzing possible docked binding modes of literature inhibitors and novel synthetic ideas. Compounds such as 19 are potent ALK5 inhibitors with good physicochemical and pharmacokinetic properties and thus represent high quality leads for further optimization.
Goldberg
Frederick W
FW
AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
Ward
Richard A
RA
Powell
Steven J
SJ
Debreczeni
Judit E
JE
Norman
Richard A
RA
Roberts
Nicola J
NJ
Dishington
Allan P
AP
Gingell
Helen J
HJ
Wickson
Kate F
KF
Roberts
Andrew L
AL
D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat