Selective class I phosphoinositide 3-kinase inhibitors: optimization of a series of pyridyltriazines leading to the identification of a clinical candidate, AMG 511.
The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. markn@amgen.com
Mark H
MH
Norman
Kristin L
KL
Andrews
Yunxin Y
YY
Bo
Shon K
SK
Booker
Sean
S
Caenepeel
Victor J
VJ
Cee
Noel D
ND
D'Angelo
Daniel J
DJ
Freeman
Bradley J
BJ
Herberich
Fang-Tsao
FT
Hong
Claire L M
CL
Jackson
Jian
J
Jiang
Brian A
BA
Lanman
Longbin
L
Liu
John D
JD
McCarter
Erin L
EL
Mullady
Nobuko
N
Nishimura
Liping H
LH
Pettus
Anthony B
AB
Reed
Tisha San
TS
Miguel
Adrian L
AL
Smith
Markian M
MM
Stec
Seifu
S
Tadesse
Andrew
A
Tasker
Divesh
D
Aidasani
Xiaochun
X
Zhu
Raju
R
Subramanian
Nuria A
NA
Tamayo
Ling
L
Wang
Douglas A
DA
Whittington
Bin
B
Wu
Tian
T
Wu
Ryan P
RP
Wurz
Kevin
K
Yang
Leeanne
L
Zalameda
Nancy
N
Zhang
Paul E
PE
Hughes
D018360:Crystallography, X-Ray; D008958:Models, Molecular; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*
D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines