2. Academic Validation
  3. Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activity

Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activity

  • J Med Chem. 2008 Oct 9;51(19):5897-900. doi: 10.1021/jm800832q.
Upender Velaparthi 1,  Mark Wittman,  Peiying Liu,  Joan M Carboni,  Francis Y Lee,  Ricardo Attar,  Praveen Balimane,  Wendy Clarke,  Michael W Sinz,  Warren Hurlburt,  Karishma Patel,  Lorell Discenza,  Sean Kim,  Marco Gottardis,  Ann Greer,  Aixin Li,  Mark Saulnier,  Zheng Yang,  Kurt Zimmermann,  George Trainor,  Dolatrai Vyas
Affiliations

Affiliation

  • 1 Discovery Chemistry, Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Co., Wallingford, Connecticut 06492, USA. upender.velaparthi@bms.com
PMID: 18763755 DOI: 10.1021/jm800832q
Abstract

We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.

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