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

  • Bioorg Med Chem Lett. 2010 May 15;20(10):3182-5. doi: 10.1016/j.bmcl.2010.03.057.
Upender Velaparthi  1 ,  Mark G Saulnier ,  Mark D Wittman ,  Peiying Liu ,  David B Frennesson ,  Kurt Zimmermann ,  Joan M Carboni ,  Marco Gottardis ,  Aixin Li ,  Ann Greer ,  Wendy Clarke ,  Zheng Yang ,  Krista Menard ,  Francis Y Lee ,  George Trainor ,  Dolatrai Vyas
Affiliations
  • 1. Department of Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, CT 06492, USA. [email protected]
PMID: 20399649 DOI: 10.1016/j.bmcl.2010.03.057
Abstract

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.

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