Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.
The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
Cee
Victor J
VJ
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Bldg. 1000, Cambridge, Massachusetts 02139, USA. vcee@amgen.com
Albrecht
Brian K
BK
Geuns-Meyer
Stephanie
S
Hughes
Paul
P
Bellon
Steve
S
Bready
James
J
Caenepeel
Sean
S
Chaffee
Stuart C
SC
Coxon
Angela
A
Emery
Maurice
M
Fretland
Jenne
J
Gallant
Paul
P
Gu
Yan
Y
Hodous
Brian L
BL
Hoffman
Doug
D
Johnson
Rebecca E
RE
Kendall
Richard
R
Kim
Joseph L
JL
Long
Alexander M
AM
McGowan
David
D
Morrison
Michael
M
Olivieri
Philip R
PR
Patel
Vinod F
VF
Polverino
Anthony
A
Powers
David
D
Rose
Paul
P
Wang
Ling
L
Zhao
Huilin
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000480:Alkynes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000480:Alkynes; D000577:Amides; D020533:Angiogenesis Inhibitors; D001798:Blood Proteins; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D042787:Receptor, TIE-2