Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.
A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters.
Hodous
Brian L
BL
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. bhodous@amgen.com
Geuns-Meyer
Stephanie D
SD
Hughes
Paul E
PE
Albrecht
Brian K
BK
Bellon
Steve
S
Caenepeel
Sean
S
Cee
Victor J
VJ
Chaffee
Stuart C
SC
Emery
Maurice
M
Fretland
Jenne
J
Gallant
Paul
P
Gu
Yan
Y
Johnson
Rebecca E
RE
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
Wang
Ling
L
Zhao
Huilin
H
D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
D014227:Triazines; D042787:Receptor, TIE-2