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

• Published in: Journal of medicinal chemistry Vol. 58; no. 19; pp. 7775 - 7784
• Main Authors: Liu, Chunjian, Lin, James, Hynes, John, Wu, Hong, Wrobleski, Stephen T., Lin, Shuqun, Dhar, T. G. Murali, Vrudhula, Vivekananda M., Sun, Jung-Hui, Chao, Sam, Zhao, Rulin, Wang, Bei, Chen, Bang-Chi, Everlof, Gerry, Gesenberg, Christoph, Zhang, Hongjian, Marathe, Punit H., McIntyre, Kim W., Taylor, Tracy L., Gillooly, Kathleen, Shuster, David J., McKinnon, Murray, Dodd, John H., Barrish, Joel C., Schieven, Gary L., Leftheris, Katerina
• Format: Journal Article
• Language: English
• Published: American Chemical Society 08-10-2015
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00839

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.