SAR of PXR transactivation in benzimidazole-based IGF-1R kinase inhibitors.
The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.
Oncology Chemistry, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA. Kurt.Zimmermann@bms.com
Kurt
K
Zimmermann
Mark D
MD
Wittman
Mark G
MG
Saulnier
Upender
U
Velaparthi
Xiaopeng
X
Sang
David B
DB
Frennesson
Charles
C
Struzynski
Steven P
SP
Seitz
Liqi
L
He
Joan M
JM
Carboni
Aixin
A
Li
Ann F
AF
Greer
Marco
M
Gottardis
Ricardo M
RM
Attar
Zheng
Z
Yang
Praveen
P
Balimane
Lorell N
LN
Discenza
Francis Y
FY
Lee
Michael
M
Sinz
Sean
S
Kim
Dolatrai
D
Vyas
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000077297:Pregnane X Receptor; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D000077297:Pregnane X Receptor; D047428:Protein Kinase Inhibitors; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A; D017526:Receptor, IGF Type 1