2. Academic Validation
  3. 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

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

Affiliation

  • 1 Department of Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, CT 06492, USA. upender.velaparthi@bms.com
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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