Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
Hodous
Brian L
BL
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139-1581, USA. bhodous@amgen.com
Geuns-Meyer
Stephanie D
SD
Hughes
Paul E
PE
Albrecht
Brian K
BK
Bellon
Steve
S
Bready
James
J
Caenepeel
Sean
S
Cee
Victor J
VJ
Chaffee
Stuart C
SC
Coxon
Angela
A
Emery
Maurice
M
Fretland
Jenne
J
Gallant
Paul
P
Gu
Yan
Y
Hoffman
Doug
D
Johnson
Rebecca E
RE
Kendall
Richard
R
Kim
Joseph L
JL
Long
Alexander M
AM
Morrison
Michael
M
Olivieri
Philip R
PR
Patel
Vinod F
VF
Polverino
Anthony
A
Rose
Paul
P
Tempest
Paul
P
Wang
Ling
L
Whittington
Douglas A
DA
Zhao
Huilin
H
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D001549:Benzamides; D001798:Blood Proteins; C518307:N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-yloxy)benzamide; D011725:Pyridines; D014227:Triazines; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2