Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.
The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
Cee
Victor J
VJ
Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142 and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. vcee@amgen.com
Schenkel
Laurie B
LB
Hodous
Brian L
BL
Deak
Holly L
HL
Nguyen
Hanh N
HN
Olivieri
Philip R
PR
Romero
Karina
K
Bak
Annette
A
Be
Xuhai
X
Bellon
Steve
S
Bush
Tammy L
TL
Cheng
Alan C
AC
Chung
Grace
G
Coats
Steve
S
Eden
Patrick M
PM
Hanestad
Kelly
K
Gallant
Paul L
PL
Gu
Yan
Y
Huang
Xin
X
Kendall
Richard L
RL
Lin
Min-Hwa Jasmine
MH
Morrison
Michael J
MJ
Patel
Vinod F
VF
Radinsky
Robert
R
Rose
Paul E
PE
Ross
Sandra
S
Sun
Ji-Rong
JR
Tang
Jin
J
Zhao
Huilin
H
Payton
Marc
M
Geuns-Meyer
Stephanie D
SD
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010793:Phthalazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C552336:4-(4-fluorophenyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine; D000970:Antineoplastic Agents; D001798:Blood Proteins; D006657:Histones; D010793:Phthalazines; D011725:Pyridines; D011743:Pyrimidines; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases