N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics.
2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.
Bamborough
Paul
P
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Paul.A.Bamborough@gsk.com
Angell
Richard M
RM
Bhamra
Inder
I
Brown
David
D
Bull
James
J
Christopher
John A
JA
Cooper
Anthony W J
AW
Fazal
Lynsey H
LH
Giordano
Ilaria
I
Hind
Lucy
L
Patel
Vipulkumar K
VK
Ranshaw
Lisa E
LE
Sims
Martin J
MJ
Skone
Philip A
PA
Smith
Kathryn J
KJ
Vickerstaff
Emma
E
Washington
Melanie
M
D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007191:Indazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008958:Models, Molecular
D004791:Enzyme Inhibitors; D007191:Indazoles; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)