TY - JOUR
T1 - 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
AU - Liu, Chunjian
AU - Lin, James
AU - Hynes, John
AU - Wu, Hong
AU - Wrobleski, Stephen T.
AU - Lin, Shuqun
AU - Dhar, T. G.Murali
AU - Vrudhula, Vivekananda M.
AU - Sun, Jung Hui
AU - Chao, Sam
AU - Zhao, Rulin
AU - Wang, Bei
AU - Chen, Bang Chi
AU - Everlof, Gerry
AU - Gesenberg, Christoph
AU - Zhang, Hongjian
AU - Marathe, Punit H.
AU - McIntyre, Kim W.
AU - Taylor, Tracy L.
AU - Gillooly, Kathleen
AU - Shuster, David J.
AU - McKinnon, Murray
AU - Dodd, John H.
AU - Barrish, Joel C.
AU - Schieven, Gary L.
AU - Leftheris, Katerina
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/10/8
Y1 - 2015/10/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84943775745
UR - https://www.scopus.com/pages/publications/84943775745#tab=citedBy
U2 - 10.1021/acs.jmedchem.5b00839
DO - 10.1021/acs.jmedchem.5b00839
M3 - Article
C2 - 26359680
AN - SCOPUS:84943775745
SN - 0022-2623
VL - 58
SP - 7775
EP - 7784
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -