Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors.
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.
Belanger
David B
DB
Department of Medicinal Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. david.belanger@merck.com
Williams
Michael J
MJ
Curran
Patrick J
PJ
Mandal
Amit K
AK
Meng
Zhaoyang
Z
Rainka
Matthew P
MP
Yu
Tao
T
Shih
Neng-Yang
NY
Siddiqui
M Arshad
MA
Liu
Ming
M
Tevar
Seema
S
Lee
Suining
S
Liang
Lianzhu
L
Gray
Kimberly
K
Yaremko
Bohdan
B
Jones
Jennifer
J
Smith
Elizabeth B
EB
Prelusky
Dan B
DB
Basso
Andrea D
AD
D000284:Administration, Oral; D000818:Animals; D064127:Aurora Kinases; D001682:Biological Availability; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C556838:imidazo(1,2-a)pyrazine; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases