Structure-based optimization of aminopyridines as PKCθ inhibitors.
The identification of a novel series of PKCθ inhibitors and subsequent optimization using docking based on a crystal structure of PKCθ is described. SAR was rapidly generated around an amino pyridine-ketone hit; (6-aminopyridin-2-yl)(2-aminopyridin-3-yl)methanone 2 leading to compound 21 which significantly inhibits production of IL-2 in a mouse SEB-IL2 model.
Department of Chemistry at Vertex Pharmaceuticals (Europe) Ltd, 88 Milton Park, Abingdon OX14 4RY, United Kingdom. juan-miguel_jimenez@vrtx.com
Juan-Miguel
JM
Jimenez
Christopher
C
Davis
Dean
D
Boyall
Damien
D
Fraysse
Ronald
R
Knegtel
Luca
L
Settimo
Stephen
S
Young
Claire
C
Bolton
Peter
P
Chiu
Adam
A
Curnock
Richele
R
Rasmussen
Adam
A
Tanner
Ian
I
Ager
D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C