2,5-Diaminopyrimidines and 3,5-disubstituted azapurines as inhibitors of glycogen synthase kinase-3 (GSK-3).
The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50)<10nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters.
Lum
Christopher
C
Kemia, Inc., 5871 Oberlin Dr., Ste. 100, San Diego, CA 92121, USA. chrislum@sbcglobal.net
Kahl
Jeff
J
Kessler
Linda
L
Kucharski
Jeff
J
Lundström
Jan
J
Miller
Stephen
S
Nakanishi
Hiroshi
H
Pei
Yazhong
Y
Pryor
Kent
K
Roberts
Edward
E
Sebo
Lubomir
L
Sullivan
Robert
R
Urban
Jan
J
Wang
Zhijun
Z
D000284:Administration, Oral; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D047428:Protein Kinase Inhibitors; D011687:Purines; D011743:Pyrimidines; C576920:Aurka protein, rat; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3