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聽(BMS-751324), a Cl

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• 作者：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 Gillooly ; David J. Shuster ; Murray McKinnon ; John H. Dodd ; Joel C. Barrish ; Gary L. Schieven ; Katerina Leftheris
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 8, 2015
• 年：2015
• 卷：58
• 期：19
• 页码：7775-7784
• 全文大小：405K
• ISSN：1520-4804

文摘

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 p38伪 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 TNF伪 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.