Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2.
Described herein is the design and synthesis of indazolylaminopyridopyrimidines and quinazolines as inhibitors of the class 1 tyrosine kinase receptor family. Data is presented for N(4)-(1-benzyl-1H-indazol-5-yl)-N(6),N(6)-dimethylpyrido[3,4-d]pyrimidine-4,6-diamine 3B. This compound inhibited EGFr and c-erbB-2 enzymes selectively over other kinases. It inhibited the proliferation of a range of tumour cell lines in vitro and the growth of BT474 xenografts in SCID mice.
Cockerill
S
S
Enzyme Chemistry 1, Oncology Unit, Enzyme Pharmacology, Research Biomet. Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Hertfordshire SG1 2NY, Stevenage, UK. scockerill@arrowt.co.uk
Stubberfield
C
C
Stables
J
J
Carter
M
M
Guntrip
S
S
Smith
K
K
McKeown
S
S
Shaw
R
R
Topley
P
P
Thomsen
L
L
Affleck
K
K
Jowett
A
A
Hayes
D
D
Willson
M
M
Woollard
P
P
Spalding
D
D
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C433938:4557 W; C433939:GW 974 cpd