Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors: SAR of a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one.
A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
Velaparthi
Upender
U
Department of Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, CT 06492, USA. upender.velaparthi@bms.com
Saulnier
Mark G
MG
Wittman
Mark D
MD
Liu
Peiying
P
Frennesson
David B
DB
Zimmermann
Kurt
K
Carboni
Joan M
JM
Gottardis
Marco
M
Li
Aixin
A
Greer
Ann
A
Clarke
Wendy
W
Yang
Zheng
Z
Menard
Krista
K
Lee
Francis Y
FY
Trainor
George
G
Vyas
Dolatrai
D
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
C504983:BMS 536924; C551144:BMS 577098; D001562:Benzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C031000:benzimidazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017526:Receptor, IGF Type 1