Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor

Chunjian Liu, James Lin, John Hynes, Hong Wu, Stephen T. Wrobleski, Shuqun Lin, T. G.Murali Dhar, Vivekananda M. Vrudhula, Jung Hui Sun, Sam Chao, Rulin Zhao, Bei Wang, Bang Chi Chen, Gerry Everlof, Christoph Gesenberg, Hongjian Zhang, Punit H. Marathe, Kim W. McIntyre, Tracy L. Taylor, Kathleen GilloolyDavid J. Shuster, Murray McKinnon, John H. Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.

Original languageEnglish (US)
Pages (from-to)7775-7784
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number19
StatePublished - Oct 8 2015

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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