2-(1H-Imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chain variants of the IGF-1R inhibitor BMS-536924.
A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.
Saulnier
Mark G
MG
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Mark.Saulnier@bms.com
Frennesson
David B
DB
Wittman
Mark D
MD
Zimmermann
Kurt
K
Velaparthi
Upender
U
Langley
David R
DR
Struzynski
Charles
C
Sang
Xiaopeng
X
Carboni
Joan
J
Li
Aixin
A
Greer
Ann
A
Yang
Zheng
Z
Balimane
Praveen
P
Gottardis
Marco
M
Attar
Ricardo
R
Vyas
Dolatrai
D
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011485:Protein Binding; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D044967:Serum; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C504983:BMS 536924; D001562:Benzimidazoles; D011728:Pyridones; D017526:Receptor, IGF Type 1