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.
Zimmermann
Kurt
K
Oncology Chemistry, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA. Kurt.Zimmermann@bms.com
Wittman
Mark D
MD
Saulnier
Mark G
MG
Velaparthi
Upender
U
Sang
Xiaopeng
X
Frennesson
David B
DB
Struzynski
Charles
C
Seitz
Steven P
SP
He
Liqi
L
Carboni
Joan M
JM
Li
Aixin
A
Greer
Ann F
AF
Gottardis
Marco
M
Attar
Ricardo M
RM
Yang
Zheng
Z
Balimane
Praveen
P
Discenza
Lorell N
LN
Lee
Francis Y
FY
Sinz
Michael
M
Kim
Sean
S
Vyas
Dolatrai
D
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