Bioorganic and Medicinal Chemistry Letters p. 3182 - 3185 (2010)
Update date:2022-08-04
Topics:
Velaparthi, Upender
Saulnier, Mark G.
Wittman, Mark D.
Liu, Peiying
Frennesson, David B.
Zimmermann, Kurt
Carboni, Joan M.
Gottardis, Marco
Li, Aixin
Greer, Ann
Clarke, Wendy
Yang, Zheng
Menard, Krista
Lee, Francis Y.
Trainor, George
Vyas, Dolatrai
A series of 3-[6-(4-substitued-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.
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